EA040198B1 - CRYSTAL FORM A -EN-1-SHE - Google Patents

Description

The present application claims priority under U.S. Provisional Application No. 61/655,381 entitled Crystalline Forms of a Bruton's Tyrosine Kinase Inhibitor, filed June 4, 2012, which is hereby incorporated by reference in its entirety.

The field of technology to which the invention belongs

The present application describes a Bruton's tyrosine kinase (Btk) inhibitor crystal form A 1 -((R)-3-(4-amino-3-(4-phenoxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidine-1 - yl) piperidin-1 -yl) prop-2-en-1 she. Also disclosed is a pharmaceutical composition for the treatment of diseases or pathological conditions that are beneficially affected by the inhibition of Btk activity, which includes the specified crystalline form, and a method for its preparation.

Background Art Information

Bruton's tyrosine kinase (Btk), a member of the Tec family of non-receptor tyrosine kinases, is a key enzyme of the signaling system expressed by all types of hematopoietic cells with the exception of T-lymphocytes and natural killer cells. Btk plays a critical role in the B-cell metabolic signaling pathway by linking stimulation of a cellular receptor on the B-cell surface (the B-cell (antigen-recognition) receptor, BCR) to subsequent intracellular responses.

Btk is a key regulator of B cell development, activation, signaling, and survival. In addition, Btk is involved in a number of metabolic signaling pathways of other hematopoietic cells, such as TNF-α production in macrophages mediated by the Toll-like receptor (TLR) and cytokine receptors, IgE receptor signaling (called Fc epsilon RI) in mast cells. , in the inhibition of Fas/APO-1 apoptotic signal in lymphoid cells of the B-cell line and in collagen stimulation of platelet aggregation.

IUPAC nomenclature 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1yl)piperidin-1-yl)prop-2-ene -1-one is called 1-{(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1Hpyrazolo[3,4-d]pyrimidin-1 -yl]piperidin-1-yl}prop- 2-en-1-one or 2-propen-1-one, 1-[(3R)-3-[4-amino3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-1- yl]-1-piperidinyl- and it was given the USAN name ibrutinib. In this invention, various names of ibrutinib are used as synonyms.

The essence of the invention

This application discloses Crystal Form A 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl) prop-2-en-1-she. A pharmaceutical composition is also disclosed, which includes the specified crystalline form, and a method for its preparation.

In one aspect, the present invention includes crystalline form A 1-((R)-3-(4-amino-3(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1 -yl)piperidin-1 yl) prop-2-en-1-one, which is characterized by at least one of the following properties:

(a) an X-ray powder diffraction pattern (XRPD) substantially the same as the X-ray powder diffraction pattern shown in FIG. 1;

(b) X-ray powder diffraction (XRPD) with characteristic peaks at 2θ angles of 5.7±0.1°, 13.6±0.1°, 16.1±0.1°, 18.9±0.1°, 21.3±0.1°, and 21.6±0.1°;

(c) substantially the same X-ray powder diffraction pattern (XRPD) after storage at 40° C. and 75% relative humidity (RH) for at least a week;

(d) substantially the same X-ray powder diffraction pattern (XRPD) after storage at 25° C. and 97% relative humidity (RH) for at least a week;

(e) IR (IR) spectrum is practically similar to the IR spectrum shown in FIG. 2;

(e) in the IR (IR) spectrum there are weak bands with a frequency of about 1584 cm ^-1 , about 1240 cm ^-1 , about 1147 cm ^-1 , about 1134 cm ^-1 , about 1099 cm ^-1 and about 1067 cm ^-1 ;

(g) The DSC thermogram is essentially the same as the DSC thermogram shown in FIG. 3;

(h) thermogravimetric (TGA) curve (thermogram) is practically similar to the TGA thermogram shown in FIG. 4;

(i) DSC thermogram showing an endothermic effect starting at about 154°C and a peak (maximum) at about 157°C and an exothermic effect at about 159°C;

(k) lack of hygroscopicity;

(l) an experimental value for solubility in water of about 0.013 mg/ml at a pH of about 8; or (m) combinations thereof.

In some embodiments, the powder x-ray pattern (XRPD) of crystalline Form A has substantially the same pattern as the x-ray powder pattern shown in FIG. 1. In some embodiments, the powder X-ray diffraction pattern (XRPD) of crystalline Form A has characteristic peaks at 2θ angles of 5.7±0.1°, 13.6±0.1°, 16.1±0.1°, 18.9±0.1°, 21.3±0.1°, and 21.6±0.1 °. In some embodiments, the powder x-ray diffraction pattern (XRPD) of crystalline form A remains substantially the same after storage at 40° C. and 75% relative humidity (RH) for at least a week. According to some options powder X-ray diffraction (XRPD)

- 1 040198 crystalline form A remains practically the same after storage at 25°C and relative humidity (RH) 97% for at least a week. In some embodiments, the IR (IR) spectrum is substantially the same as the IR spectrum shown in FIG. 2. In some embodiments, the IR (IR) spectrum of crystalline form A has faint bands with a frequency of about 1584 cm ^-1 , about 1240 cm ^-1 , about 1147 cm ^-1 , about 1134 cm ^-1 , about 1099 cm ^-1 and about 1067 cm ^-1 . In some embodiments, crystalline form A has a melting point of about 155-156°C. In some embodiments, the DSC thermogram of crystalline form A is substantially the same as the DSC thermogram shown in FIG. 3. In some embodiments, the thermogravimetric (TGA) curve (thermogram) of crystalline form A is substantially similar to the TGA thermogram shown in FIG. 4. In some embodiments, the DSC thermogram of crystalline Form A exhibits an endothermic effect starting at about 154°C, with a peak (maximum) at about 157°C, and an exothermic effect at about 159°C. In some embodiments, crystalline form A is not hygroscopic. In some embodiments, the experimental solubility of crystalline form A in water is about 0.013 mg/ml at a pH of about 8. In some embodiments, crystalline form A is characterized by the properties presented in paragraphs. (a), (b), (c), (d), (e), (f), (g), (h), (i), (j), and (k). In some embodiments, crystalline form A was obtained (crystallized) from ethyl acetate, isopropyl acetate, tetrahydrofuran, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), nitromethane, methanol, ethanol, acetonitrile, dioxane, methyl tertiary butyl ether (MTBE), anisole, acetone, heptanes , methanol/water mixtures or acetone/heptane mixtures. In some embodiments, crystalline Form A is obtained (crystallized) from methanol/water. In some embodiments, crystalline form A is unsolvated. In some embodiments, crystalline form A is anhydrous.

In another aspect of the present invention, crystal form A of 1-((R)-3-(4amino-3-(4-phenoxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1- yl) prop-2-en-1-one, for which one or more of the following is true:

(a) the crystalline form is characterized by powder X-ray diffraction (XRPD) with characteristic peaks at 2-θ angle values of 5.7±0.1° obtained using CuKa radiation;

(b) the crystalline form is characterized by XRPD with characteristic peaks at 2-θ angle values of 18.9±0.1° obtained using CuKa radiation;

(c) the crystalline form is characterized by XRPD with characteristic peaks at 2-θ angle values of 21.3±0.1° obtained using CuKa radiation;

(d) the crystalline form is characterized by XRPD with characteristic peaks as shown in FIG. 1;

(e) the crystalline form is characterized by an infrared (IR) spectrum with bands with a frequency of 1584 cm ^-1 , 1240 cm ^-1 , 1147 cm ^-1 , 1134 cm ^-1 , 1099 cm ^-1 and 1067 cm ^-1 ; or (f) the crystalline form is characterized by a differential scanning calorimetry (DSC) thermogram peaking at 157° C., the DSC thermogram obtained by heating the crystalline form at a rate of 10° C./min.

In some embodiments of the XRPD, the X-ray pattern contains a characteristic peak at 2-θ angles of 5.7±0.1° obtained using CuKa radiation.

According to some variants of XRPD, the X-ray peak at 2-θ angles of 13.6±0.1°.

According to some versions of XRPD, the X-ray peak is at 2-θ angles of 16.1±0.1°.

According to some versions of XRPD, the X-ray peak is at 2-θ angles of 18.9±0.1°.

According to some versions of XRPD, the X-ray peak at 2-θ angles of 21.3±0.1°.

According to some variants of XRPD, the X-ray peak at 2-θ angles of 21.6±0.1°.

According to some versions of XRPD, the X-ray peak at 2-θ angles of 21.3±0.1°.

According to some variants of the XRPD X-ray pattern additionally additionally additionally additionally additionally additionally contains contains contains contains contains contains contains contains characteristic characteristic characteristic characteristic peak at angle 2-θ values equal to 13.6±0.1°, 16.1±0.1°, and 21.6±0.1°.

In some embodiments of the XRPD, the X-ray pattern contains a characteristic peak at 2-θ angles of 18.9±0.1° obtained using CuKa radiation.

In some embodiments of the XRPD, the X-ray pattern additionally contains a characteristic peak at 2-θ angles of 13.6±0.1°.

In some embodiments of the XRPD, the X-ray pattern additionally contains a characteristic peak at 2-θ angles of 16.1±0.1°.

According to some variants of the XRPD, the X-ray pattern additionally contains a characteristic peak at 2-θ angles of 21.3±0.1°.

In some embodiments of the XRPD, the X-ray pattern additionally contains a characteristic peak at 2-θ angles of 13.6±0.1°.

In some embodiments of the XRPD, the X-ray pattern additionally contains a characteristic peak at 2-θ angles of 16.1±0.1°.

In some embodiments of the XRPD, the X-ray pattern additionally contains a characteristic peak at 2-θ angles of 21.6±0.1°.

According to some options, the IR spectrum contains bands with a frequency of 1584 cm ^-1 , 1240 cm ^-1 , 1147 cm ^-1 , 1134 cm ^-1 , 1099 cm ^-1 and 1067 cm ^-1 .

In some embodiments, the DSC thermogram exhibits an endothermic effect peaking at 157° C., the DSC thermogram obtained by heating the crystalline form at a rate of 10° C./min.

In some embodiments, the endothermic effect is observed starting at 154°C.

In some embodiments, an exothermic effect is additionally observed on the DSC thermogram at 159°C.

In some embodiments, the thermogravimetric (TGA) crystal shape curve is as shown in FIG. 4.

In some embodiments, crystalline form A is one or more of the following:

(a) powder X-ray pattern (XRPD) of the crystalline form does not change after storage at 40°C and relative humidity (RH) 75% for at least a week;

(b) powder X-ray pattern (XRPD) of the crystalline form does not change after storage at 25°C and relative humidity (RH) 97% for at least a week;

(c) the crystalline form is non-hygroscopic; or (d) the change in mass of the crystalline form, as measured by dynamic vapor sorption (DVS), was less than 0.3% w/w. in the range of 0-90% RH.

In some embodiments, the crystalline form is unsolvated.

In another aspect of the present invention, a pharmaceutical composition is provided comprising:

(a) crystalline Form A;

(b) a filler; and (c) a lubricant.

In another aspect of the present invention, a pharmaceutical composition is provided comprising:

(a) 40 to 200 mg of crystalline Form A;

(b) 40 to 50 wt.% filler; and (c) 0.2 to 1.0 wt.% lubricant.

In some embodiments, the pharmaceutical composition further comprises a disintegrant.

In some embodiments, the pharmaceutical composition further comprises a surfactant.

In another aspect of the present invention, a pharmaceutical composition is provided comprising:

(a) 40 to 200 mg of crystalline Form A;

(b) from 40 to 50 wt.% filler;

(c) from 3 to 10 wt.% baking powder;

(d) 2 to 7% by weight of a surfactant; and (e) 0.2 to 1.0% by weight of a lubricant.

In some embodiments, the filler is selected from lactose, sucrose, dextrose, dextrates, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrins, calcium phosphate, calcium sulfate, starches, modified starches, microcrystalline cellulose, microcellulose, and talc.

In some embodiments, the filler is microcrystalline cellulose.

In some embodiments, the disintegrant is selected from natural starch, pregelatinized starch, sodium starch glycolate, crystalline methylcellulose, methylcellulose, croscarmellose, croscarmellose sodium, crosslinked sodium carboxymethylcellulose, crosslinked carboxymethylcellulose, crosslinked croscarmellose, crosslinked starch such as sodium starch glycolate, crosslinked polymer such as crospovidone, cross-linked polyvinylpyrrolidone, sodium alginate, clay and gum.

In some embodiments, the disintegrant is selected from natural starch, pregelatinized starch, sodium starch glycolate, crystalline methylcellulose, methylcellulose, croscarmellose, croscarmellose sodium, crospovidone, sodium alginate, clay, and gum.

- 3 040198

In some embodiments, the disintegrant is croscarmellose sodium.

In some embodiments, the surfactant is selected from sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, poloxamers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide.

In some embodiments, the surfactant is sodium lauryl sulfate.

In some embodiments, the lubricant is selected from stearic acid, calcium hydroxide, talc, cornstarch, sodium stearyl fumarate, sodium stearate, magnesium stearate, zinc stearate, and waxes.

In some embodiments, the lubricant is magnesium stearate.

In some embodiments, the filler is selected from lactose, sucrose, dextrose, dextrates, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrins, calcium phosphate, calcium sulfate, starches, modified starches, microcrystalline cellulose, microcellulose, and talc;

the disintegrant is selected from natural starch, pregelatinized starch, sodium starch glycolate, crystalline methylcellulose, methylcellulose, croscarmellose, croscarmellose sodium, crosslinked sodium carboxymethylcellulose, crosslinked carboxymethylcellulose, crosslinked croscarmellose, crosslinked starch such as sodium starch glycolate, crosslinked polymer, crosslinked polyvinylpyrrolidone, sodium alginate , clays or gums;

the surfactant is selected from sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, poloxamers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide; and the lubricant is selected from stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, sodium stearate, magnesium stearate, zinc stearate and waxes.

In another aspect of the present invention, a pharmaceutical composition is provided comprising:

(a) 40 to 50% by weight of crystalline Form A;

(b) from 40 to 50 wt.% microcrystalline cellulose;

(c) 3 to 10% by weight of croscarmellose sodium;

(d) 2 to 7 wt% sodium lauryl sulfate; and (e) 0.2 to 1.0 wt% magnesium stearate.

In another aspect of the present invention, a pharmaceutical composition is provided comprising:

(a) 40 to 200 mg of form A;

(b) 40 to 50% by weight of microcrystalline cellulose; and (c) 0.2 to 1.0% by weight of magnesium stearate.

41. Pharmaceutical composition for oral administration containing:

(a) 40 to 200 mg of crystalline form;

(b) from 40 to 50 wt.% microcrystalline cellulose;

(c) 3 to 10% by weight of croscarmellose sodium;

(d) 2 to 7 wt% sodium lauryl sulfate; and (e) 0.2 to 1.0 wt% magnesium stearate.

In another aspect of the present invention, a pharmaceutical composition is provided comprising:

(a) 140 mg of crystalline Form A;

(b) 151.4 mg microcrystalline cellulose;

(c) 23.0 mg croscarmellose sodium;

(d) 14.0 mg sodium lauryl sulfate; and (e) 1.6 mg magnesium stearate.

In another aspect of the present invention, a pharmaceutical composition is provided comprising:

(b) 45.9 wt% microcrystalline cellulose;

(c) 7.0 wt% croscarmellose sodium;

(d) 4.2 wt% sodium lauryl sulfate; and (e) 0.5 wt% magnesium stearate.

In some embodiments, the pharmaceutical composition is in a dosage form that is a hard gelatin capsule.

In another aspect of the present invention, there is provided a process for the preparation of a pharmaceutical composition of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine -1 yl) prop-2-en-1-one, comprising mixing one or more excipients with the isolated crystalline form according to any one of claims 1-7023.

In some embodiments, the method further comprises grinding the resulting mixture

- 4 040198 one or more excipients and crystalline form.

In some embodiments, the method further comprises placing a mixture of one or more excipients and a crystalline form in a gelatin capsule.

In some embodiments, the method further comprises placing a mixture of one or more excipients and crystalline Form A in a non-gelatin capsule.

In some embodiments, the pharmaceutical composition is placed in a hard gelatin capsule. In some embodiments, the pharmaceutical composition is in a form suitable for oral administration to a mammal. In some embodiments, the pharmaceutical composition is in the form of a solid oral dosage form. In some embodiments, the pharmaceutical composition contains from about 0.5 mg to about 1000 mg of crystalline 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidine- 1 -yl) piperidin-1 -yl) prop-2-en-1 she.

In another aspect of the present invention, a pharmaceutical composition for oral administration is provided, comprising:

(a) about 40 mg to about 200 mg of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4d]pyrimidin-1-yl)piperidin-1 -yl) prop-2-en-1 -one;

(b) from about 40 wt.% to about 50 wt.% filler;

(c) from about 3 wt.% to about 10 wt.% baking powder (disintegrator);

(d) from about 2% to about 7% by weight of a surfactant; and (e) from about 0.2% to about 1.0% by weight of a lubricant.

In some embodiments, the filler is selected from the group consisting of lactose, sucrose, dextrose, dextrates, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrins, calcium phosphate, calcium sulfate, starches, modified starches, microcrystalline cellulose, and talc. In some embodiments, the filler is microcrystalline cellulose. In some embodiments, the disintegrant is selected from the group consisting of natural starch, pregelatinized starch, sodium starch glycolate, crystalline methylcellulose, methylcellulose, croscarmellose, croscarmellose sodium, crosslinked sodium carboxymethylcellulose, crosslinked carboxymethylcellulose, crosslinked croscarmellose, crosslinked starch such as sodium starch glycolate, crosslinked a polymer such as crospovidone, crosslinked polyvinylpyrrolidone, sodium alginate, clay or gum (resin). In some embodiments, the disintegrant is croscarmellose sodium. In some embodiments, the surfactant is selected from the group consisting of sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, poloxamers, bile salts, glyceryl monostearate, ethylene oxide-propylene oxide copolymers. In some embodiments, the surfactant is sodium lauryl sulfate. In some embodiments, the lubricant is selected from the group consisting of stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, sodium stearate, magnesium stearate, zinc stearate, and waxes. In some embodiments, the lubricant is magnesium stearate.

In some embodiments, the present invention provides a pharmaceutical composition for oral administration comprising:

(a) about 40 mg to about 200 mg 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4d]pyrimidin-1-yl)piperidin-1 -yl) prop-2-en-1 -one;

(b) from about 40 wt.% to about 50 wt.% microcrystalline cellulose;

(c) from about 3% to about 10% by weight of croscarmellose sodium;

(d) from about 2 wt.% to about 7 wt.% sodium lauryl sulfate; and (e) from about 0.2 wt.% to about 1.0 wt.% magnesium stearate.

In some embodiments, the present invention provides a pharmaceutical composition for oral administration comprising:

(a) from about 40% to about 50% by weight 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1Hpyrazolo[3,4-d]pyrimidin-1-yl )piperidin-1-yl)prop-2-en-1-one;

(b) from about 40 wt.% to about 50 wt.% microcrystalline cellulose;

(c) from about 3% to about 10% by weight of croscarmellose sodium;

(d) from about 2 wt.% to about 7 wt.% sodium lauryl sulfate; and (e) from about 0.2 wt.% to about 1.0 wt.% magnesium stearate.

In some embodiments, the present invention provides a pharmaceutical composition for oral administration comprising:

(a) 140 mg 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1yl)prop-2 -en-1-she;

(b) 45.9 wt% microcrystalline cellulose;

(c) 7 wt% croscarmellose sodium;

(d) 4.2 wt% sodium lauryl sulfate; and (e) 0.5 wt% magnesium stearate.

- 5 040198

In some embodiments, the present invention provides a pharmaceutical composition for oral administration comprising:

(a) 140 mg 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1yl)prop-2 -en-1 -one;

(b) 151.4 mg microcrystalline cellulose;

(c) 23.0 mg croscarmellose sodium;

(d) 14.0 mg sodium lauryl sulfate; and (e) 1.6 mg magnesium stearate.

In another aspect of the present invention, a pharmaceutical composition for oral administration is provided, comprising:

(a) about 40 mg to about 200 mg of crystalline 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)1 H-pyrazolo[3,4-d]pyrimidin-1-yl) piperidin-1-yl)prop-2-en-1-one;

(b) from about 40 wt.% to about 50 wt.% filler;

(c) from about 3 wt.% to about 10 wt.% baking powder (disintegrator);

(d) from about 2% to about 7% by weight of a surfactant; and (e) from about 0.2% to about 1.0% by weight of a lubricant.

In some embodiments, the filler is selected from the group consisting of lactose, sucrose, dextrose, dextrates, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrins, calcium phosphate, calcium sulfate, starches, modified starches, microcrystalline cellulose, microcellulose, and talc. In some embodiments, the filler is microcrystalline cellulose. In some embodiments, the disintegrant is selected from the group consisting of natural starch, pregelatinized starch, sodium starch glycolate, crystalline methylcellulose, methylcellulose, croscarmellose, croscarmellose sodium, crosslinked sodium carboxymethylcellulose, crosslinked carboxymethylcellulose, crosslinked croscarmellose, crosslinked starch such as sodium starch glycolate, crosslinked a polymer such as crospovidone, crosslinked polyvinylpyrrolidone, sodium alginate, clay or gum (resin). In some embodiments, the disintegrant is croscarmellose sodium. In some embodiments, the surfactant is selected from the group consisting of sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, poloxamers, bile salts, glyceryl monostearate, ethylene oxide-propylene oxide copolymers. In some embodiments, the surfactant is sodium lauryl sulfate. In some embodiments, the lubricant (lubricant) is selected from the group consisting of stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, sodium stearate, magnesium stearate, zinc stearate, and waxes. In some embodiments, the lubricant is magnesium stearate.

In some embodiments, the present invention provides a pharmaceutical composition for oral administration comprising:

(a) about 40 mg to about 200 mg of crystalline 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)1 H-pyrazolo[3,4-d]pyrimidin-1-yl) piperidin-1-yl)prop-2-en-1-one;

(b) from about 40 wt.% to about 50 wt.% microcrystalline cellulose;

(c) from about 3% to about 10% by weight of croscarmellose sodium;

(d) from about 2 wt.% to about 7 wt.% sodium lauryl sulfate; and (e) from about 0.2 wt.% to about 1.0 wt.% magnesium stearate.

In some embodiments, the present invention provides a pharmaceutical composition for oral administration comprising:

(a) from about 40% to about 50% by weight of crystalline 1-((R)-3-(4-amino-3-(4phenoxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidine-1 -yl) piperidin-1 -yl) prop-2-en-1 -one;

(b) from about 40 wt.% to about 50 wt.% microcrystalline cellulose;

(c) from about 3% to about 10% by weight of croscarmellose sodium;

(d) from about 2 wt.% to about 7 wt.% sodium lauryl sulfate; and (e) from about 0.2 wt.% to about 1.0 wt.% magnesium stearate.

In some embodiments, the present invention provides a pharmaceutical composition for oral administration comprising:

(a) 140 mg of crystalline 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin1-yl)piperidin-1-yl)prop- 2-en-1-she;

(b) 45.9 wt% microcrystalline cellulose;

(c) 7 wt% croscarmellose sodium;

(d) 4.2 wt% sodium lauryl sulfate; and (e) 0.5 wt% magnesium stearate.

In some embodiments, the present invention provides a pharmaceutical composition for oral administration comprising:

(a) 140 mg of crystalline 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin1-yl)piperidin-1-yl)prop- 2-en-1-she;

- 6 040198 (b) 151.4 mg of microcrystalline cellulose;

(c) 23.0 mg croscarmellose sodium;

(d) 14.0 mg sodium lauryl sulfate; and (e) 1.6 mg magnesium stearate.

According to some of the above embodiments of the pharmaceutical composition, crystalline -yl)prop-2en-1-one is the crystalline form A. According to another embodiment above, the present invention provides a pharmaceutical composition, the dosage form of which is a hard gelatin capsule.

In another aspect of the present invention, a pharmaceutical composition for oral administration is provided, comprising:

(a) from about 40 mg to about 200 mg of crystalline form A 1-((R)-3-(4-amino-3-(4phenoxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1-yl )piperidin-1-yl)prop-2-en-1-one;

(b) from about 40 wt.% to about 50 wt.% filler;

(c) from about 3 wt.% to about 10 wt.% baking powder;

(d) from about 2% to about 7% by weight of a surfactant; and (e) from about 0.2% to about 1.0% by weight of a lubricant.

In some embodiments, the filler is selected from the group consisting of lactose, sucrose, dextrose, dextrates, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrins, calcium phosphate, calcium sulfate, starches, modified starches, microcrystalline cellulose, microcellulose, and talc. In some embodiments, the filler is microcrystalline cellulose. In some embodiments, the disintegrant is selected from the group consisting of natural starch, pregelatinized starch, sodium starch, crystalline methylcellulose, methylcellulose, croscarmellose, croscarmellose sodium, crosslinked sodium carboxymethylcellulose, crosslinked carboxymethylcellulose, crosslinked croscarmellose, crosslinked starch such as sodium starch glycolate, crosslinked polymer , such as crospovidone, cross-linked polyvinylpyrrolidone, sodium alginate, clay or gum (resin). In some embodiments, the disintegrant is croscarmellose sodium. In some embodiments, the surfactant is selected from the group consisting of sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, poloxamers, bile salts, glyceryl monostearate, ethylene oxide-propylene oxide copolymers. In some embodiments, the surfactant is sodium lauryl sulfate. In some embodiments, the lubricant (lubricant) is selected from the group consisting of stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, sodium stearate, magnesium stearate, zinc stearate, and waxes. In some embodiments, the lubricant is magnesium stearate.

In some embodiments, the present invention provides a pharmaceutical composition for oral administration comprising:

(a) from about 40 mg to about 200 mg of crystalline Form A )piperidin-1-yl)prop-2-en-1-one;

(b) from about 40 wt.% to about 50 wt.% microcrystalline cellulose;

(c) from about 3% to about 10% by weight of croscarmellose sodium;

(d) from about 2 wt.% to about 7 wt.% sodium lauryl sulfate; and (e) from about 0.2 wt.% to about 1.0 wt.% magnesium stearate.

In some embodiments, the present invention provides a pharmaceutical composition for oral administration comprising:

(a) from about 40 wt.% to about 50 wt.% of the crystalline form A 1-((R)-3-(4-amino-3-(4phenoxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidine -1 -yl)piperidin-1 -yl)prop-2-en-1 -one;

(b) from about 40 wt.% to about 50 wt.% microcrystalline cellulose;

(c) from about 3% to about 10% by weight of croscarmellose sodium;

(d) from about 2 wt.% to about 7 wt.% sodium lauryl sulfate; and (e) from about 0.2 wt.% to about 1.0 wt.% magnesium stearate.

In some embodiments, the present invention provides a pharmaceutical composition for oral administration comprising:

(a) 140 mg of crystalline form A 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4d]pyrimidin-1-yl)piperidin-1-yl) prop-2-en-1-one;

(b) 45.9 wt% microcrystalline cellulose;

(c) 7 wt% croscarmellose sodium;

(d) 4.2 wt% sodium lauryl sulfate; and (e) 0.5 wt% magnesium stearate.

In some embodiments, the present invention provides a pharmaceutical composition for oral administration comprising:

(a) 140 mg of crystalline form A 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4

- 7 040198

d]nupuMuguH-1 -yl)piperidin-1 -yl)prop-2-en-1-one;

(b) 151.4 mg microcrystalline cellulose;

(c) 23.0 mg croscarmellose sodium;

(d) 14.0 mg sodium lauryl sulfate; and (e) 1.6 mg magnesium stearate.

In another aspect of the present invention, a pharmaceutical composition is provided comprising:

(a) about 40 mg to about 200 mg 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4d]pyrimidin-1-yl)piperidin-1 -yl) prop-2-en-1 -one;

(b) from about 40 wt.% to about 50 wt.% filler;

(c) from about 3 wt.% to about 10 wt.% baking powder;

(d) from about 2% to about 7% by weight of a surfactant; and (e) from about 0.2% to about 1.0% by weight of a lubricant;

moreover, the composition is in the form of a standard (single, single) dosage form in a blister pack, and the specified blister pack is made of metal foil or polymer film.

In some embodiments, the present invention provides a pharmaceutical composition comprising:

(a) 140 mg 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1yl)prop-2 -en-1-she;

(b) 45.9 wt% microcrystalline cellulose;

(c) 7 wt% croscarmellose sodium;

(d) 4.2 wt.% sodium lauryl sulfate and (e) 0.5 wt.% magnesium stearate, and the composition is in the form of a standard dosage form in a blister pack, and the specified blister pack is made of metal foil or polymer film.

According to another embodiment, the present invention provides a blister pack containing one or more pockets, where each pocket contains a unit dosage form, including:

(a) about 40 mg to about 200 mg 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4d]pyrimidin-1-yl)piperidin-1 -yl) prop-2-en-1 -one;

(b) from about 40 wt.% to about 50 wt.% filler;

(c) from about 3 wt.% to about 10 wt.% baking powder;

(d) from about 2% to about 7% by weight of a surfactant; and (e) from about 0.2% to about 1.0% by weight of a lubricant;

moreover, the material of each pocket of the blister pack is a metal foil or a polymer film.

In another aspect of the present invention, a pharmaceutical composition is provided comprising:

(a) from about 40 wt.% to about 50 wt.% of the crystalline Form A 1-((R)-3-(4-amino-3-(4phenoxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidine -1 -yl)piperidin-1 -yl)prop-2-en-1 -one;

(b) from about 40 wt.% to about 50 wt.% filler;

(c) from about 3 wt.% to about 10 wt.% baking powder;

(d) from about 2% to about 7% by weight of a surfactant; and (e) from about 0.2% to about 1.0% by weight of a lubricant;

moreover, the composition is in the form of a standard dosage form in a blister pack, and the material for said blister pack is a metal foil or a polymer film.

In some embodiments, the present invention provides a pharmaceutical composition comprising:

(a) 140 mg 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1yl)prop-2 -en-1-she;

(b) 45.9 wt% microcrystalline cellulose;

(c) 7 wt% croscarmellose sodium;

(d) 4.2 wt.% sodium lauryl sulfate and (e) 0.5 wt.% magnesium stearate, and the composition is in the form of a standard dosage form in a blister pack, and the specified blister pack is made of metal foil or polymer film.

According to another embodiment, the present invention provides a blister pack containing one or more pockets, where each pocket contains a unit dosage form, including:

(a) from about 40 mg to about 200 mg of crystalline Form A 1-((R)-3-(4-α-myno-3-(4

- 8 040198 phenoxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)piperidin-1 -yl)prop-2-en-1-one;

(b) from about 40 wt.% to about 50 wt.% filler;

(c) from about 3 wt.% to about 10 wt.% baking powder;

(d) from about 2% to about 7% by weight of a surfactant; and (e) from about 0.2% to about 1.0% by weight of a lubricant;

moreover, the material of each pocket of the blister pack is a metal foil or a polymer film.

According to one embodiment, the present invention provides a kit that contains a collection of (multiple) oral dosage forms, such as tablets or capsules, packaging, such as a container (vessel) in which the oral dosage forms are located, and instructions for use for administering the oral dosage forms. in accordance with the method of the present invention. Unit dose packages, such as blister packs, are a good way to package the oral dosage form of the compositions of the present invention, and in other embodiments, this package is embodied as a kit in combination with instructions for use. In other embodiments, detailed information about the product is contained in the instructions for use in the kit. The blister pack is particularly useful in the case of solid oral dosage forms, and in other embodiments of the invention, it is used, for example, in dosing regimens every other day. In one embodiment, it is sufficient to take one or more tablets or capsules of the compositions of the present invention daily in solid dosage forms in a blister pack with instructions for use. In another embodiment, it is sufficient to take every other day solid dosage forms in the form of one or more tablets or capsules of the compositions of the present invention, placed in a blister pack with instructions for use.

In some embodiments, crystalline Compound 1 is used to formulate a medicament for inhibiting Bruton's tyrosine kinase (Btk) activity.

In some embodiments, the cancer is a B-cell malignancy. In some embodiments, the cancer is a B-cell malignancy selected from chronic lymphocytic leukemia (CLL)/small lymphocyte lymphoma (SLL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL, DLBCL), and multiple myeloma. In some embodiments, the cancer is a lymphoma, leukemia, or a solid tumor. In some embodiments, the cancer is diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic leukocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma/Waldenström macroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal B-cell marginal zone lymphoma, nodal marginal zone B-cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt's lymphoma/leukemia, or lymphomatoid granulomatosis. In some embodiments, when the subject has a cancer, the anti-cancer agent is administered to the subject along with one of the above compounds. In one embodiment, the anticancer agent is a mitogen-activated protein kinase signaling inhibitor.

The present invention provides articles comprising a packaging material, Compound 1 within the packaging material, and a label (leaflet) stating that Compound 1 is used to inhibit the activity of a tyrosine kinase(s) such as Btk.

In another aspect of the invention, the use of compound 1 is contemplated for the preparation of a medicament for the treatment of an inflammatory disease or condition in an animal in which the activity of Btk or other tyrosine kinases homologous to Btk is due to the presence of a cysteine residue (including Cys 481 residue) that can form a covalent communication with at least one irreversible inhibitor of the present invention, contributes to the manifestation of the pathology and/or symptoms of the disease or pathological condition. In one embodiment of this aspect of the invention, the tyrosine kinase protein is Btk. In another or additional embodiment of this aspect of the invention, the inflammatory diseases or conditions are respiratory, cardiovascular, or proliferative diseases.

Any of the above aspects include additional options, in which the connection 1 (a) is administered to the mammal systemically; (b) administered orally to the mammal; (c) administered intravenously to a mammal; (d) administered by inhalation; (e) administered nasally; or (e) administered to a mammal by injection; (g) administered topically (dermally) to the mammal; (h) administered to the mammal in the eye; (i) administered rectally to a mammal.

Any of the above aspects have additional options, including a single administration of an effective amount of compound 1, including options in which compound 1 (i) is administered once; (ii) enter several times within one day; (iii) repeatedly or (iv) continuously.

Any of the above aspects have additional options, including multiple administration of compound 1, including additional options in which (i) compound 1 is administered as a single dose; (ii) the time between administrations for multiple administrations is 6 hours; (iii) Compound 1 is administered to the mammal every 8 hours. In other or alternative embodiments, the method comprises a drug holiday during which the administration of Compound 1 is temporarily stopped or the dose of the compound administered is gradually reduced; at the end of drug holidays, dosing of Compound 1 was resumed. The duration of the medicinal holidays can vary from 2 days to 1 year.

In some embodiments, in any embodiments of the present invention (including methods, uses, compositions, complex therapy, etc.), Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is optically pure (i.e., as determined by HPLC ) his (her) chiral purity is above 99%). In some embodiments, in any embodiments of the present invention (including methods, uses, compositions, complex therapy, etc.), Compound 1 or a pharmaceutically acceptable salt or solvate thereof is replaced by a) Compound 1 or a pharmaceutically acceptable salt or solvate thereof with a lower chiral purity; b) 1-((S)-3-(4-amino-3-(4phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en- 1-one or a pharmaceutically acceptable salt or solvate thereof of any optical purity; or c) racemic 1-(3-(4-amino-3(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1 -one or a pharmaceutically acceptable salt or solvate thereof.

Other objects, features and advantages of the methods and compositions described in this application will become apparent from the following detailed description. However, it should be understood that the detailed description and specific examples, while showing specific embodiments of the invention, are provided for purposes of illustration only, as various changes and modifications consistent with the spirit and scope of the present invention will become apparent to those skilled in the art from this detailed description. Section headings in this application are given for organizational purposes only and should not be construed as limiting the subject matter being described. All documents or excerpts from (part of) documents cited in this application, including, but not limited to, patents, patent applications, articles, books, reference books and scientific works, are hereby expressly incorporated into the present invention by reference in their entirety for any goals.

Inclusion of information by referral

All publications and patent applications referred to in this specification are hereby incorporated by reference where appropriate and relevant.

Brief description of the figures

In FIG. 1 shows an x-ray powder diffraction pattern (XRPD) of Form A.

In FIG. 2 shows the infrared (IR, IR) spectrum of Form A.

In FIG. 3 shows the DSC thermogram of form A.

In FIG. 4 shows a thermogravimetric (TGA) curve (thermogram) of Form A.

In FIG. 5 shows an x-ray powder diffraction pattern (XRPD) of Form B.

In FIG. 6 shows the infrared (IR, IR) spectrum of Form B.

In FIG. 7 shows the DSC thermogram form B.

In FIG. 8 shows a thermogravimetric (TGA) curve (thermogram) of form B.

In FIG. 9 shows an x-ray powder diffraction pattern (XRPD) of Form C.

In FIG. 10 shows a DSC thermogram of Form C.

In FIG. 11 shows a thermogravimetric (TGA) curve (thermogram) of Form C.

In FIG. 12 shows an X-ray powder diffraction pattern (XRPD) of Form D.

In FIG. 14 shows a thermogravimetric (TGA) curve (thermogram) of Form D.

In FIG. 14 shows an X-ray powder diffraction pattern (XRPD) of Form E.

In FIG. 15 shows a DSC thermogram and a thermogravimetric (TGA) curve (thermogram) of Form E.

In FIG. 16 shows an X-ray powder diffraction pattern (XRPD) of Form F.

Information confirming the possibility of carrying out the invention

The various roles played by the Btk signaling pathway in various hematopoietic cell functions, such as activation of B-cell receptors, suggest that small molecule inhibitors of Btk, such as Compound 1, are useful for reducing risk or for treating a range of diseases that are affected by and which affect many cell types of the hematopoietic lineage, including, for example, autoimmune diseases, heteroimmune conditions or diseases, inflammatory diseases, cancer (eg, B-cell proliferative disorders), and thromboembolic diseases (disorders). The irreversible Btk inhibitors of the present invention, such as Compound 1, can also be used to inhibit a small subset of other tyrosine kinases that are homologous to Btk due to the presence of a cysteine residue (including Cys 481) that can form a covalent bond with an irreversible inhibitor.

In some embodiments, Compound 1 may be used to treat an autoimmune disease in a mammal, which includes, but is not limited to, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still-Choffard disease, juvenile arthritis, lupus, diabetes, myasthenia gravis, thyroiditis. Hashimoto, Horde's thyroiditis, Graves' disease, Sjögren's syndrome, multiple sclerosis, Guillain-Barré syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome (dancing eye syndrome), ankylosing spondylitis, antiphospholipid syndrome, aplastic anemia, autoimmune hepatitis, celiac disease disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis (retrobulbar neuritis), scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal (giant cell) arteritis, heat antibody-induced autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, general alopecia, Behcet's disease, chronic fatigue, autonomic dystonia, endometriosis, interstitial cystitis, neuromyotonia, scleroderma and vulvodynia.

In some embodiments, Compound 1 can be used to treat heteroimmune diseases or pathological conditions, which include, but are not limited to, homologous disease (secondary, graft-versus-host disease), transplantation, blood transfusion, anaphylaxis, allergy (e.g., allergy to plant pollen , latex, drugs, foods, insect venoms, animal dander, animal dander, house dust mites or cockroaches), type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis.

In some embodiments, Compound 1 may be used to treat an inflammatory disease in a mammal, which includes, but is not limited to, asthma, inflammatory bowel disease, appendicitis, blepharitis, capillary bronchitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, cystitis, dacryodenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, hepatitis, suppurative hidradenitis, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonitis (pulmonitis), pneumonia, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, uveitis, vaginitis, vasculitis and vulvitis.

In some embodiments, the methods of the present invention may be used to treat cancer, such as B-cell proliferative disorders, which include, but are not limited to, diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia. , lymphoplasmacytic/Waldenström macroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular (intravascular) large B-cell lymphoma, primary effusion lymphoma, Burkitt's lymphoma/leukemia, and lymphomatoid granulomatosis.

In other embodiments, the methods of the present invention can be used to treat thromboembolic diseases (thromboembolic disorders), which include, but are not limited to, myocardial infarction, angina (including unstable angina), reocclusion or restenosis after angioplasty or after coronary artery bypass grafting, stroke, transient ischemic attack, peripheral vascular occlusive disease, pulmonary embolism or deep vein thrombosis.

Hematological malignancies.

In some embodiments, the present invention provides a method of treating a hematologic malignancy in a subject in need thereof, comprising administering to that subject an amount of Compound 1.

In some embodiments, the hematologic malignancy is non-Hodgkin's lymphoma (NHL). In some embodiments, the hematologic malignancy is chronic lymphocytic leukemia (CLL), small lymphocyte (SLL) lymphoma, high-risk CLL lymphoma, or non-CLL/SLL lymphoma. In some embodiments, the hematologic malignancy is follicular lymphoma (FL), diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenström macroglobulinemia, multiple myeloma (MM), marginal zone lymphoma, Burkitt's lymphoma, non-Burkitt's High-grade B-cell lymphoma or extranodal marginal zone B-cell lymphoma. In some embodiments, the hematologic cancer is acute or chronic myelogenous (or myeloid) leukemia, myelodysplastic syndrome, acute lymphoblastic leukemia, or B lymphocyte progenitor acute lymphoblastic leukemia. In some embodiments, the hematologic malignancy is chronic lymphoblastic leukemia (CLL). In some embodiments, the hematologic malignancy is a lymphoma of cells

- 11 040198 mantle zone (MCL). In some embodiments, the hematologic malignancy is diffuse large B-cell lymphoma (DLBCL). In some embodiments, the hematologic malignancy is diffuse large B cell lymphoma (DLBCL), ABC subtype. In some embodiments, the hematologic malignancy is diffuse large B cell lymphoma (DLBCL), GCB subtype. In some embodiments, the hematologic malignancy is Waldenström's macroglobulinemia (WM). In some embodiments, the hematologic malignancy is multiple myeloma (MM). In some embodiments, the hematologic malignancy is Burkitt's lymphoma. In some embodiments, the hematologic cancer is follicular lymphoma (FL). In some embodiments, the hematologic malignancy is a transformed follicular lymphoma (transformed cell lymphoma). In some embodiments, the hematologic malignancy is a marginal zone lymphoma.

In some embodiments, the hematologic malignancy is relapsed or refractory (persistent, untreatable) non-Hodgkin's lymphoma (NHL). In some embodiments, the hematologic malignancy is recurrent or refractory diffuse large B cell lymphoma (DLBCL), recurrent or refractory mantle cell lymphoma (MCL), recurrent or refractory follicular lymphoma (FL), recurrent or refractory CLL, relapsed or refractory SLL, relapsed or refractory multiple myeloma, relapsed or refractory Waldenström macroglobulinemia, relapsed or refractory multiple myeloma (MM), relapsed or refractory marginal zone lymphoma, relapsed or refractory Burkitt's lymphoma, recurrent or refractory high-grade non-Burkitt B-cell lymphoma, recurrent or refractory extranodal marginal zone B-cell lymphoma. In some embodiments, the hematologic malignancy is recurrent or refractory acute or chronic myelogenous (or myeloid) leukemia, recurrent or refractory myelodysplastic syndrome, recurrent or refractory acute lymphoblastic leukemia, or recurrent or refractory cellular acute lymphoblastic leukemia. precursors of B-lymphocytes. In some embodiments, the hematologic malignancy is relapsing or refractory chronic lymphoblastic leukemia (CLL). In some embodiments, the hematologic malignancy is recurrent or refractory mantle cell lymphoma (MCL). In some embodiments, the hematologic cancer is recurrent or refractory diffuse large B cell lymphoma (DLBCL). In some embodiments, the hematologic malignancy is recurrent or refractory diffuse large B cell lymphoma (DLBCL), ABC subtype. In some embodiments, the hematologic malignancy is recurrent or refractory diffuse large B cell lymphoma (DLBCL), GCB subtype. In some embodiments, the hematologic malignancy is relapsing or refractory Waldenström macroglobulinemia (WM). In some embodiments, the hematologic malignancy is relapsing or refractory multiple myeloma (MM). In some embodiments, the hematologic malignancy is relapsing or refractory Burkitt's lymphoma. In some embodiments, the hematologic malignancy is recurrent or refractory follicular lymphoma (FL).

In some embodiments, the hematologic cancer is a hematologic cancer that is classified as a high risk cancer. In some embodiments, the hematologic cancer is high risk CLL or high risk SLL.

B-lymphoproliferative disorders (BCLDs) are neoplasms (tumors) of the blood and include, in particular, non-Hodgkin's lymphoma, multiple myeloma and leukemia. BCLDs can occur either in the lymphatic tissues (as in the case of lymphoma) or in the bone marrow (as in the case of leukemia or myeloma), and all are associated with an uncontrolled growth of lymphocytes or leukocytes. There are many subtypes of BCLD, such as chronic lymphocytic leukemia (CLL) and non-Hodgkin's lymphoma (NHL). The course of the disease and treatment of BCLD depends on the type of BCLD; however, even within each subtype, clinical manifestations, morphology, and response to therapy differ.

Malignant lymphomas are neoplastic cell transformations that

- 12 040198 are located mainly in lymphoid tissues. Two groups of malignant lymphomas are Hodgkin's lymphoma and non-Hodgkin's lymphoma (NHL). Both types of lymphomas invade the reticuloendothelial system (macrophage system). However, they differ in the origin of the neoplastic cells, the primary site of disease, the presence of systemic symptoms, and the response to treatment (treatment outcome) (Freedman et al., Non-Hodgkin's Lymphomas Chapter 134, Cancer Medicine, (American Cancer Society approved edition, B.C. Decker Inc. , Hamilton, Ontario, 2003).

Non-Hodgkin's lymphomas.

In some embodiments, the present invention provides a method of treating non-Hodgkin's lymphoma in a subject in need thereof, comprising administering to that subject an amount of Compound 1.

In some embodiments, the present invention also provides a method of treating recurrent or refractory non-Hodgkin's lymphoma in a subject in need thereof, comprising administering to that subject a therapeutically effective amount of Compound 1. In some embodiments, non-Hodgkin's lymphoma is relapsing or refractory diffuse large B-cell lymphoma (DLBCL), recurrent or refractory mantle cell lymphoma, recurrent or refractory follicular lymphoma, or recurrent or refractory CLL.

Non-Hodgkin's lymphomas (NHL) are a diverse group of malignant tumors predominantly of B-cell origin. NHL can appear in any part of the lymphatic system, such as the spleen, lymph nodes, or tonsils, and at any age. NHL is often characterized by swollen lymph nodes, fever, and weight loss. NHL refers to either B-cell or T-cell NHL. Lymphomas related to lymphoproliferative disorders followed by bone marrow or stem cell transplantation are usually B-cell NHL. The current classification system divides NHL into low, intermediate (intermediate), and high grade categories based on the natural course of the disease (see The Non-Hodgkin's Lymphoma Pathologic Classification Project, Cancer 49(1982): 2112-2135). Low-grade lymphomas are indolent (sluggish) with a median survival of 5 to 10 years (Horning and Rosenberg (1984) N. Engl. J. Med. 311: 1471-1475). Although chemotherapy can cause remission of most indolent lymphomas, recovery is rare, and most patients relapse sooner or later, requiring additional treatment. Medium (intermediate) and high grade lymphomas are more aggressive tumors but have a higher chance of being cured with chemotherapy. However, a significant proportion of these patients relapse and require additional treatment.

A non-limiting list of B-cell NHLs includes Burkitt's lymphoma (e.g., endemic Burkitt's lymphoma and sporadic Burkitt's lymphoma), cutaneous B-cell lymphoma, cutaneous marginal zone lymphoma (MZL), diffuse large cell lymphoma (DLBCL), diffuse mixed small- and large cell lymphoma, diffuse small lymphocytic cleaved cell lymphoma, diffuse small lymphocytic lymphoma, extranodal marginal zone B-cell lymphoma, follicular lymphoma, follicular cleaved small cell lymphoma (Grade 1), follicular mixed cleaved cell small and large cell lymphoma ( grade 2), follicular large cell lymphoma (grade 3), intravascular (intravascular) large B-cell lymphoma, intravascular lymphomatosis, large immunoblastic lymphoma, large cell lymphoma (LCL), immunoblastic lymphoma, MALT lymphoma, mantle cell lymphoma (mantle cell lymphoma, MCL) B-cell progenitor lymphoblastic lymphoma, chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), extranodal marginal zone B-cell lymphoma-mucosal-associated lymphoid tissue (MALT) lymphoma, mediastinal large B-cell lymphoma (mediastinal lymphoma), nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma, primary mediastinal B-cell lymphoma, lymphoplasmacytic lymphoma, hairy cell leukemia, Waldenström's macroglobulinemia, and primary central nervous system (CNS, CNS) lymphoma. Other non-Hodgkin's lymphomas are within the scope of the present invention and are known to those skilled in the art.

DLBCL (DLBCL).

In some embodiments, the present invention provides a method of treating DLCBL in a subject in need, comprising administering to that subject an amount of Compound 1. In some embodiments, the present invention also provides a method of treating recurrent or refractory DLCBL in a subject in need, comprising administering to that subject therapeutically an effective amount of compound 1.

In this context, the term diffuse large B-cell lymphoma (DLBCL, DLBCL)

- 13 040198 refers to a neoplasm of B-lymphocytes originating from the germinal (germinal) center (lymph node) with a diffuse growth pattern and a high-to-average (intermediate) proliferation index. DLBCLs account for approximately 30% of all lymphomas and may exist in several morphological variants, including subtypes: centroblastic, immunoblastic, T cell/histiocyte enriched, anaplastic, and plasmablastic. Genetic tests have shown that there are various subtypes of DLBCL. These subtypes appear to have different prospects (prognosis) and treatment outcomes. DLBCL can affect any age group but is most common in older people (average age around 65).

In some embodiments, the present invention provides a method of treating diffuse large B-cell lymphoma, activated B-cell subtype (ABC-DLBCL), in a subject in need thereof, comprising administering to that subject an irreversible Btk inhibitor in an amount of 300 mg/day up to 1000 mg/day. Diffuse large B cell lymphoma of the ABC subtype (ABC-DLBCL) is believed to be formed by post-germ B cells that are blocked (suppressed) during differentiation into plasma cells. DLBCL The ABC subtype (ABC-DLBCL) accounts for approximately 30% of DLBCL cases. It is believed that of all the molecular subtypes of DLBCL, it is the least curable, and for this reason, the survival rate of patients diagnosed with ABC-DLBCL is significantly lower compared to patients with other types of DLCBL. Usually, ABC-DLBCL is associated with chromosomal translocations that deregulate the main regulator of the germinal (germinal) center BCL6, and with mutations that inactivate the PRDM1 gene, which encodes a transcription-repressing protein (repressor) necessary for plasma cell differentiation.

A particularly relevant signaling pathway in the pathogenesis of ABC-DLBCL is the signaling pathway mediated by the nuclear transcription factor (NF)-kB complex. The NF-κB family includes 5 members (p50, p52, p65, c-rel, and RelB) that form homo- and heterodimers and behave as transcription factors, mediating a range of proliferative, apoptotic, inflammatory, and immune responses, and are essential for normal development and viability of B-cells. NFκB is widely used by eukaryotic cells as a regulator of genes that control cell proliferation and cell viability. Accordingly, NF-kB is misregulated in many different types of human tumors, i. NF-kB is constitutively (permanently) active. Active NF-kB turns on the expression of genes that support cell proliferation and protect the cell from conditions that could cause its death through apoptosis.

The dependence of ABC DLBCLs on NF-kB is determined by the pre-IkB kinase signaling pathway, consisting of CARD11, BCL10, and MALT1 (CBM complex). Superposition of the CBM pathway quenches the NF-kB signal in ABC DLBCL cells and induces apoptosis. The molecular basis of the constitutive activity of the NF-kB signal is the subject of the present study, but some somatic changes in the ABC genome of DLBCLs undoubtedly activate this pathway. For example, somatic mutations in the coiled-coil domain of CARD11 in DLBCL give this signaling scaffold protein the ability to spontaneously become the center of protein-protein interaction with MALT1 and BCL10, causing PSC activity and NF-kB activation. The constitutive activity of the B-cell receptor signaling pathway entails the activation of NF-kB in ABC DLBCLs by wild-type CARD11, and it is directly related to mutations at the cytoplasmic end of the CD79A and CD79B B-cell receptor subunits. Activating mutations of the oncogene in the MYD88 signaling pathway adapter activate NF-kB and, by amplifying (adding to) the B-cell receptor signal, support the survival (viability) of ABC DLBCL cells. In addition, inactivating mutations in the negative regulator of the NF-kB signaling pathway, A20, occur almost exclusively in ABC DLBCL.

Indeed, genetic changes affecting many components of the NF-kB signaling pathway have recently been identified in more than 50% of patients with ABC-DLBCL, and these changes stimulate the constitutive activation of NF-kB, thereby promoting the growth of lymphoma. These changes include mutations in CARD11 (y ~10% of patients), a lymphocyte-specific cytoplasmic scaffold protein that forms, together with MALT1 and BCL10, the BCR signaling complex (signalosome), which (which) transmits signals from antigen receptors to subsequent mediators of NF-kB activation . An even larger proportion of patients (~30%) are carriers of biallelic genetic changes that inactivate the negative regulator of the NF-kB signaling pathway, A20. Also, high expression levels of target genes of the NF-kB pathway were observed in tumor ABC-DLBCL samples. See, for example, U. Klein et al., (2008), Nature Reviews Immunology 8: 22-23; R.E. Davis et al., (2001), Journal of Experimental Medicine 194: 1861-1874; G. Lentz et al., (2008), Science 319: 1676-1679; M. Compagno et al., (2009), Nature 459: 712-721; and L. Srinivasan et al., (2009), Cell 139: 573-586).

DLBCL cells of the ABC subtype, such as OCI-Ly10, receive constant active signals from the BCR and are highly sensitive to the Btk inhibitor of the present disclosure. The irreversible Btk inhibitor of the present application effectively and irreversibly inhibits the growth of OCI-Ly10 (EC ₅₀ continuous exposure = 10 nM, EC ₅₀ 1 hour pulsed = 50 nM). In addition, induction is observed in OCI-Ly10

- 14 040198 apoptosis as shown by capsase activation, flow cytometry using annexin V protein and as shown by an increase in the sub-G0 fraction. Btk expression levels are similar in both susceptible and resistant cells, and in both cases the Btk active site is entirely occupied by the inhibitor, as shown by a fluorescently labeled affinity probe. It has been demonstrated that an active BCR signal to NF-kB is continuously transmitted in OCI-Ly10 cells, which is dose-dependently inhibited by the Btk inhibitors of the present invention. The activity of Btk inhibitors in the cell lines studied in this invention was also characterized by comparing signal transduction profiles (Btk, PLCy, ERK, NF-kB, AKT), cytokine secretion profiles and mRNA expression profiles both with and without BCR stimulation, and observed significant differences between these profiles, which made it possible to identify clinical biomarkers to identify patient populations most sensitive to treatment with Btk inhibitors. See US patent No. 7711492 and Staudt et al., Nature, Vol. 463, Jan. 7, 2010, pp. 88-92, the contents of which are hereby incorporated by reference in their entirety.

Follicular lymphoma.

In some embodiments, the present invention provides a method of treating follicular lymphoma in a subject in need, comprising administering to that subject an amount of Compound 1. In some embodiments, the present invention also provides a method of treating recurrent or refractory follicular lymphoma in a subject in need, comprising administering the to the subject a therapeutically effective amount of Compound 1.

As used herein, the term follicular lymphoma refers to any of several types of non-Hodgkin's lymphoma in which lymphomatous cells are aggregated (clustered) as nodules or follicles. The term follicle is used because the cells in the lymph nodes usually grow in a circle or sphere (node). The average age of patients with this lymphoma is about 60 years.

CLL/SLL.

In some embodiments, the present invention provides a method of treating CLL or SLL in a subject in need, comprising administering to that subject an amount of Compound 1. In some embodiments, the present invention also provides a method of treating recurrent or refractory CLL or SLL in a subject in need, comprising administering to that subject a therapeutically effective amount of Compound 1.

Chronic lymphocytic leukemia and small cell lymphocytic lymphoma (CLL/SLL) are usually considered the same disease with slightly different disease manifestations. The name CLL or SLL is determined by where the cancer cells accumulate. If cancer cells are initially found in the lymph nodes, which resemble lima beans (moon bean) structures of the lymphatic system (a system consisting mainly of tiny vessels), then the disease is called SLL. SLL accounts for approximately 5 to 10% of all lymphomas. When cancer cells are in the bloodstream and in the bone marrow, the disease is called CLL.

Both CLL and SLL are slow growing tumors, although tumors in CLL, which is much more common, tend to grow more slowly. CLL and SLL are treated in the same way. It is generally believed that they cannot be cured with standard drugs, but depending on the stage and rate of tumor growth, patients live for more than 10 years. Rarely, these slowly growing lymphomas can transform into a more aggressive type of lymphoma over time.

Chronic lymphoid leukemia (CLL) is the most common type of leukemia. An estimated 100,760 people in the United States are living with CLL or in remission. Most (>75%) people who are first diagnosed with CLL are over 50 years of age. The current treatment of CLL focuses on controlling the disease and its symptoms rather than conventional treatment. CLL is treated with chemotherapy, radiation therapy, biological therapy, and bone marrow transplantation. Symptoms are sometimes treated with surgery (by splenectomy—removal of the enlarged spleen) or with radiation therapy (cytoreduction of swollen lymph nodes). Although CLL progresses slowly in most cases, it is generally considered incurable. Some CLLs are classified as high-risk diseases. In this context, high-risk CLL means CLL characterized by at least one of the following: 1) 17p13-; 2) 11q22-; 3) unmutated IgVH along with ZAP-70+ and/or CD38+; or 4) trisomy 12 (chromosomes).

Treatment for CLL is usually given when the patient's clinical symptoms or blood count indicate that the disease has progressed to a point where it can affect the patient's quality of life.

Small cell lymphocytic leukemia (SLL) is very similar to CLL described above and is also a B-cell carcinoma. In SLL, the abnormal lymphocytes are found mainly in the lymph nodes (lymph nodes). Whereas in CLL, the abnormal lymphocytes are found mainly in the blood and bone marrow. The spleen can be affected in both diseases. SLL accounted for

- 15 040198 approximately 1 in 25 patients with all types of non-Hodgkin's lymphoma. It can appear at any age from adolescence to old age, but it rarely occurs before age 50. SLL is considered indolent (sluggish) lymphoma. This means that the disease progresses very slowly and patients usually live many years after the disease has been diagnosed. However, most patients are diagnosed with advanced disease, and although SLL responds well to a number of chemotherapy drugs, it is generally considered incurable. Although some types of cancer are generally more common in one sex than the other, SLL cases and associated deaths are evenly distributed between men and women. The median age at diagnosis is 60 years.

Although SLL is sluggish, it is constantly progressing. Usually this disease is characterized by a rapid response to radiation therapy and/or chemotherapy with some period of remission of the disease. Months or years later, an inevitable relapse occurs. A second course of treatment again has an effect, but again the disease recurs. This means that although the short-term prognosis of SLL is good, over time, many patients develop the inevitable complications of recurrent disease. Considering the age of subjects commonly diagnosed with CLL and SLL, there is a need in the art for a simple and effective drug for treating the disease with minimal side effects that does not impair the patient's quality of life. The present invention satisfies this longstanding need in the art.

Lymphoma from the cells of the mantle zone.

In some embodiments, the present invention provides a method of treating mantle cell lymphoma in a subject in need, comprising administering to that subject an amount of Compound 1. In some embodiments, the present invention also provides a method of treating recurrent or refractory mantle cell lymphoma in a subject in need of this subject, comprising administering to that subject a therapeutically effective amount of Compound 1.

As used herein, the term mantle cell lymphoma (mantle cell lymphoma) refers to a subtype of B-cell lymphoma due to a CD5 positive antigen-recognizing naive pre-germ B cell within the mantle zone that surrounds the germinal center in a normal follicle. MCL cells typically overexpress (overexpress) cyclin D1 due to t(11:14) chromosomal translocation to DNA. More specifically, this translocation is t(11;14)(q13;q32). Only about 5% of lymphomas are of this type. The cells are small (small) to medium in size. Most often, this disease affects men. The average age of the patients is 60+. By the time of diagnosis, lymphoma usually affects the lymph nodes, bone marrow, and very often the spleen. Mantle cell lymphoma is not a very fast growing lymphoma, but it is very difficult to treat.

B-cell marginal zone lymphoma.

In some embodiments, the present invention provides a method of treating marginal zone B-cell lymphoma in a subject in need, comprising administering to that subject an amount of Compound 1. In some embodiments, the present invention also provides a method of treating recurrent or refractory marginal zone B-cell lymphoma in a subject in need of this subject, comprising administering to that subject a therapeutically effective amount of Compound 1.

As used herein, the term B-cell marginal zone lymphoma refers to a group of related B-cell neoplasias that involve lymphoid tissues in the marginal zone, lesions outside the mantle zone of the follicle. Marginal zone lymphomas account for approximately 5 to 10% of lymphomas. The cells in these lymphomas look small (small) under a microscope. There are 3 main types of marginal zone lymphoma, including extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, and splenic marginal zone lymphoma.

MALT.

In some embodiments, the present invention provides a method of treating MALT in a subject in need, comprising administering to that subject an amount of Compound 1. In some embodiments, the present invention also provides a method of treating recurrent or refractory MALT in a subject in need, comprising administering to that subject therapeutically an effective amount of compound 1.

In this context, the term mucosal-associated lymphoid tissue (MALT) lymphoma refers to extranodal manifestations of marginal zone lymphomas. Most MALT lymphomas are low-grade lymphomas, while a minority of MALT lymphomas either present first as intermediate-grade non-Hodgkin's lymphoma (NHL) or develop from a low-grade form. Most MALT lymphomas occur in the stomach, and approximately 70% of gastric MALT lymphomas are associated with Helicobacter pylori infection. Several cytogenetic disorders have been identified, of which trisomy 3 or t(11;18) is the most common. Many of these other MALT lymphomas have also been associated with infections caused by bacteria or viruses. The average age of patients with MALT lymphoma is about 60 years.

Nodal B-cell marginal zone lymphoma.

In some embodiments, the present invention provides a method of treating nodal marginal zone B-cell lymphoma in a subject in need thereof, comprising administering to that subject an amount of Compound 1. In some embodiments, the present invention also provides a method of treating recurrent or refractory nodal marginal zone B-cell lymphoma. zones in a subject in need thereof, comprising administering to that subject a therapeutically effective amount of Compound 1.

As used herein, the term nodal marginal zone B-cell lymphoma refers to indolent (indolent) B-cell lymphoma that is found primarily in the lymph nodes. This disease is rare and accounts for only 1% of all non-Hodgkin's lymphomas (NHL). Most often it is diagnosed in older patients, and women are more susceptible to it than men. The disease belongs to marginal zone lymphomas, since the mutation occurs in the marginal zone of B cells. Since lymphoma is located in the lymph nodes, it is also called nodal lymphoma.

B-cell lymphoma of the marginal zone of the spleen.

In some embodiments, the present invention provides a method of treating splenic marginal zone B cell lymphoma in a subject in need, comprising administering an amount of compound 1 to that subject. In some embodiments, the present invention also provides a method of treating recurrent or refractory splenic marginal zone B cell lymphoma in a subject in need of this subject, comprising administering to that subject a therapeutically effective amount of Compound 1.

In this context, the term splenic marginal zone B-cell lymphoma refers to a specific low-grade small-cell B-cell lymphoma that is included in the classification of the World Health Organization. Its characteristic features are splenomegaly, moderate lymphocytosis with a villous structure, intrasinusoidal lesions of various organs, especially the bone marrow, and a relatively sluggish course of the disease. In a minority of patients, tumor progression with an increase in blast forms and an aggressive nature (diseases) is observed. Molecular and cytogenetic studies have yielded inconsistent results, possibly due to the lack of standard diagnostic criteria.

Burkitt's lymphoma.

In some embodiments, the present invention provides a method of treating Burkitt's lymphoma in a subject in need, comprising administering to that subject an amount of Compound 1. In some embodiments, the present invention also provides a method of treating recurrent or refractory Burkitt's lymphoma in a subject in need, comprising administering to the subject to the subject a therapeutically effective amount of Compound 1.

In this context, the term Burkitt's lymphoma refers to a type of non-Hodgkin's lymphoma (NHL) that usually affects children. This is a highly aggressive type of B-cell lymphoma that often begins and involves parts of the body other than the lymph nodes. Despite its rapid growth, Burkitt's lymphoma is often cured with the latest powerful drugs. There are two major types of Burkitt's lymphomas - sporadic (occasional) and endemic Burkitt's lymphomas:

Endemic Burkitt's lymphoma. The disease affects children much more frequently than adults and is associated with Epstein-Barr virus (EBV) infection in 95% of cases. It occurs mainly in equatorial Africa, where about half of all childhood cancers are Burkitt's lymphoma. It is characterized by a high incidence of jaw bone involvement, a hallmark that is rare in sporadic Burkitt's lymphoma. It usually also affects the abdomen.

Sporadic Burkitt's lymphoma. The Burkitt type of lymphoma, which affects the rest of the world, including Europe and North and South America, is a sporadic type. In this case, the disease is also mainly observed in children. The association with Epstein-Barr virus (EBV) is not as strong as in the case of the endemic variety, although direct signs of EBV infection are present in one in five patients. More than the lymph nodes are affected by the stomach, a noticeable involvement of which in the pathological process is observed in more than 90% of children. Bone marrow involvement is more common than in the sporadic (endemic) variety.

Macroglobulinemia Waldenström.

In some embodiments, the present invention provides a method of treating Waldenström macroglobulinemia in a subject in need, comprising administering to that subject an amount of compound 1. In some embodiments, the present invention also provides a method of treating recurrent or refractory Waldenström macroglobulinemia in a subject in need. comprising administering to that subject a therapeutically effective amount of Compound 1.

The term Waldenström's macroglobulinemia, also known as lymphoplasmic lymphoma, is a cancer involving a subtype of white blood cells called lymphocytes. The disease is characterized by uncontrolled clonal proliferation of terminally differentiated B lymphocytes. It is also characterized by lymphoma cells that produce an antibody known as immunoglobulin M (IgM). IgM antibodies circulate in the blood in large quantities, causing the liquid phase of the blood to become more viscous, like syrup. This can lead to reduced blood flow to many organs, resulting in vision problems (due to poor circulation in the blood vessels in the back of the eye (fundus)) and neurological problems (such as headache, dizziness, and confusion) due to poor blood circulation in the brain. Other symptoms may include a feeling of tiredness and weakness and a tendency to bleed. The etiology of this disease is not well understood, but several risk factors have been identified, including the 6p21.3 locus on chromosome 6. The risk of developing WM increases 2-3-fold in people with a history of autoimmune diseases with (characteristic) autoantibodies, and is particularly high the risk of the disease is associated with hepatitis, human immunodeficiency virus and rickettsiosis.

Multiple myeloma.

In some embodiments, the present invention provides a method of treating myeloma in a subject in need, comprising administering to that subject an amount of Compound 1. In some embodiments, the present invention also provides a method of treating recurrent or refractory myeloma in a subject in need, comprising administering to that subject therapeutically an effective amount of compound 1.

Multiple myeloma, also known as MM, myeloma, plasma cell myeloma, or Kahler's disease (named after Austrian physician Otto Kahler), is a cancer of the white blood cells known as plasma cells (plasmocytes). As a type of B cell, plasma cells play a key role in the immune system responsible for the production (production) of antibodies in humans and other vertebrates. They are formed in the bone marrow and transported by the lymphatic system.

Leukemia.

In some embodiments, the present invention provides a method of treating leukemia in a subject in need, comprising administering to that subject an amount of Compound 1. In some embodiments, the present invention also provides a method of treating recurrent or refractory leukemia in a subject in need, comprising administering to that subject therapeutically an effective amount of compound 1.

Leukemia is a cancer of the blood or bone marrow characterized by an abnormal increase in the number of blood cells (hemocytes), usually leukocytes (white blood cells). Leukemia is a broad term that covers a whole range of diseases. First of all, they are divided into acute and chronic forms: (i) acute leukemia is characterized by a rapid increase in the number of immature cells. This accumulation of cells makes the bone marrow unable to produce healthy hemocytes. Acute leukemia requires urgent treatment due to the rapid progression and accumulation of malignant cells, which then enter the bloodstream and affect other organs. Acute forms of leukemia are the most common forms in children; (ii) chronic leukemia is characterized by an excess production of relatively mature, but nevertheless abnormal, white blood cells. As a rule, progression takes months or years, cells are produced much faster than normal cells, as a result, there are many abnormal white blood cells in the blood. Most chronic leukemia occurs in older people, but theoretically it can manifest itself at any age. In addition, these diseases are subdivided depending on which hemocytes are affected. On this basis, leukemias are divided into lymphoblastic or lymphocytic leukemias and myeloid or myelogenous leukemias: (i) lymphoblastic or lymphocytic leukemias, characterized in that malignant changes occur in such brain cells that usually (in the normal state) develop with the formation of lymphocytes, which are infection-fighting immune system cells; (ii) myeloid or myelogenous leukemias, characterized in that malignant changes occur in those brain cells that normally (normally) develop into red blood cells, some other types of white blood cells, and platelets.

Within these major groups, there are several subgroups including, but not limited to, acute lymphoblastic leukemia (ALL), acute lymphoblastic leukemia of progenitor B cells (ALL of progenitor B lymphocytes; also known as lymphoblastic leukemia of progenitor B cells). -lymphocytes), acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML) and hairy cell leukemia (HCL). Accordingly, in some embodiments, the present invention provides a method of treating acute lymphoblastic leukemia (ALL), acute lymphoblastic leukemia of B-lymphocyte progenitor cells (ALL of progenitor B-lymphocytes; also known as lymphoblastic leukemia of progenitor B-lymphocytes), acute myelogenous leukemia (AML), chronic myelogenous

- 18 040198 leukemia (CML) and hairy cell leukemia (HCL) in a subject in need thereof, comprising administering to that subject an amount of Compound 1. In some embodiments, the leukemia is a relapsing or untreatable leukemia. In some embodiments, the leukemia is relapsing or refractory acute lymphoblastic leukemia (ALL). In some embodiments, the leukemia is relapsing or refractory B-lymphocyte progenitor acute lymphoblastic leukemia (ALL B-lymphocyte progenitor cell leukemia; also known as B-lymphocyte progenitor lymphoblastic leukemia), relapsing or refractory acute myelogenous leukemia (AML), relapsing or refractory chronic myelogenous leukemia (CML), or relapsing or refractory hairy cell leukemia (HCL).

For each of the above pathological conditions, symptoms, diagnostic tests, and prognostic tests are known. See, for example, Harrison's Principles of Internal Medicine® 16th ed., 2004, The McGraw-Hill Companies, Inc. Dey et al. (2006), Cytojournal 3(24), and the Revised European American Lymphoma (REAL) classification system (see, for example, the website maintained by the National Cancer Institute).

Various animal models are used to establish a range of therapeutically effective doses of irreversible Btk inhibitors such as Compound 1 for the treatment of any of the above diseases.

The therapeutic efficacy of compound 1 for any of the above diseases can be optimized during treatment. For example, a diagnostic evaluation of a subject being treated can be performed to correlate the improvement in symptoms of a disease or pathology with the in vivo inhibition of Btk activity achieved with a given dose of Compound 1. Cellular assays known in the art can be used to determine in vivo Btk activity, in the presence or absence of an irreversible Btk inhibitor. For example, since activated Btk is phosphorylated at tyrosine 223 (Y223) and tyrosine 551 (Y551), phospho-specific immunocytochemical staining of P-Y223 or P-Y551 positive cells can be used to detect or quantify Bkt activation in a population of cells (e.g., by assay stained cells compared with unstained cells by FACS). See, for example, Nisitani et al. (1999), Proc. Natl. Acad. Sci, USA 96: 2221-2226. Thus, the amount of Btk inhibitor administered to a subject can be increased or decreased as necessary to maintain an optimal level of Btk inhibition for treating the subject's disease state.

Compound 1 can irreversibly inhibit Btk and can be used to treat mammals suffering from pathological conditions or diseases that depend on Bruton's tyrosine kinase or mediated by Bruton's tyrosine kinase, including, but not limited to, autoimmune and other inflammatory diseases. Compound 1 has shown efficacy against a wide range of diseases and pathological conditions described in this application.

In some embodiments, Compound 1 is used in the manufacture of a medicament for the treatment of any of the pathological conditions described above (eg, autoimmune diseases, inflammatory diseases, allergic disorders, B-cell proliferative disorders, or thromboembolic diseases).

Compound 1 and its pharmaceutically acceptable salts.

The Btk inhibitor of the present invention (ie Compound 1) is selective for Btk and kinases containing a cysteine residue at a position in the tyrosine kinase amino acid sequence that is homologous to the position of cysteine residue 481 in the Btk amino acid sequence. The Btk inhibitor can form a covalent bond with Cys 481 in Btk (eg by Michael reaction).

The term compound 1 or the name 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4d]pyrimidin-1-yl)piperidin-1-yl)prop-2 -en-1 -one, or 1-{(3R)-3 -[4-amino-3-(4-phenoxyphenyl)-1Hpyrazolo[3,4-d]pyrimidin-1 -yl]piperidin-1-yl} prop-2-en-1-one, or 2-propen-1-one, 1-[(3R)-3-[4amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine -1-yl]-1-piperidinyl-, or ibrutinib, or any other suitable name refers to a compound of the following structure:

- 19 040198

Compound 1 forms a variety of pharmaceutically acceptable salts, which include acid addition salts (acid addition salts) formed by the reaction of compound 1 with organic acids, which include aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyl-containing alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, amino acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, ptoluenesulfonic acid, salicylic acid and the like;

acid addition salts (acid addition salts) formed by the reaction of compound 1 with inorganic acids, which include hydrochloric (hydrochloric) acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphoric acid, and the like.

The term "pharmaceutically acceptable salt" as applied to Compound 1 means a salt of Compound 1 that does not cause appreciable irritation to the mammal to which it is administered and does not substantially alter the biological activity and properties of the compound.

It should be understood that the term pharmaceutically acceptable salt includes solvent additive forms (solvates). Solvates contain stoichiometric amounts of solvent and are obtained by formation or isolation in solvents such as water, ethanol, methanol, methyl tertiary butyl ether (MTBE), diisopropyl ether (DIPE), ethyl acetate, isopropyl acetate, isopropyl alcohol, methyl isobutyl ketone (MIBLK), methyl ethyl ketone (MEK), acetone, nitromethane, tetrahydrofuran (THF), dichloromethane (DCM), dioxane, heptanes, toluene, anisole, acetonitrile, etc. In one aspect, solvates are formed using solvents such as, but not limited to, Class 3 solvent(s). Classes of solvents are defined, for example, at the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)) in Impurities: Guidelines for Residual Solvents, Q3C(R3), (November 2005). Hydrates are formed when the solvent is water, and alcohol addition forms are formed when the solvent is an alcohol. In some embodiments, Compound 1 solvates or pharmaceutically acceptable salts thereof are easily prepared or formed by the methods of the present invention. In certain embodiments, Compound 1 solvates are anhydrous. In some embodiments, Compound 1, or pharmaceutically acceptable salts thereof, exists in an unsolvated form. In some embodiments, Compound 1, or pharmaceutically acceptable salts thereof, exists in an unsolvated form and is anhydrous.

In other embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is prepared in various forms including, but not limited to, amorphous phase, crystalline forms, pulverized forms, and nanoparticulate forms. In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is amorphous. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is amorphous and anhydrous. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is crystalline. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is crystalline and anhydrous.

In some embodiments, Compound 1 is prepared as described in US Pat. No. 7,514,444.

Amorphous compound 1.

In some embodiments, compound 1 is amorphous and anhydrous. In some embodiments, compound 1 is amorphous. In some embodiments, Compound 1 powder X-ray diffraction (XRPD) shows no crystal structure.

- 20 040198

Compound 1, form A.

In some embodiments, compound 1 is crystalline (has a crystalline structure). In some embodiments, compound 1 is a compound of crystal form A. Crystal form A of compound 1 has at least one of the following properties:

(a) X-ray powder diffraction pattern (XRPD) substantially the same as the X-ray powder diffraction pattern shown in FIG. 1;

(b) X-ray powder diffraction (XRPD) with characteristic peaks at 2-θ angles of 5.7±0.1°, 13.6±0.1°, 16.1±0.1°, 18.9±0.1°, 21.3±0.1°, and 21.6±0.1°;

(c) substantially the same X-ray powder diffraction pattern (XRPD) after storage at 40° C. and 75% relative humidity (RH) for at least a week;

(d) substantially the same X-ray powder diffraction pattern (XRPD) after storage at 25° C. and 97% relative humidity (RH) for at least a week;

(e) The IR (IR) spectrum is essentially the same as the IR spectrum shown in FIG. 2;

(e) in the IR (IR) spectrum there are weak bands with a frequency of about 1584 cm ^-1 , about 1240 cm ^-1 , about 1147 cm ^-1 , about 1134 cm ^-1 , about 1099 cm ^-1 and about 1067 cm ^-1 ;

(g) The DSC thermogram is essentially the same as the DSC thermogram shown in FIG. 3;

(h) thermogravimetric (TGA) curve (thermogram) is practically similar to the TGA thermogram shown in FIG. 4;

(i) DSC thermogram with an endothermic effect starting at about 154°C and a peak (maximum) at about 157°C and an exothermic effect at about 159°C;

(j) lack of hygroscopicity;

(l) an experimental value for solubility in water of about 0.013 mg/ml at a pH of about 8; or (m) combinations thereof.

In some embodiments, form A of compound 1 has at least two properties selected from those listed in paragraphs. from (a) to (l). In some embodiments, form A of compound 1 is characterized by at least three properties selected from those listed in paragraphs. from (a) to (l). In some embodiments, form A of compound 1 is characterized by at least four properties selected from those listed in paragraphs. from (a) to (l). In some embodiments, form A of compound 1 has at least five properties selected from those listed in paragraphs. from (a) to (l). In some embodiments, form A of compound 1 has at least six properties selected from those listed in paragraphs. from (a) to (l). In some embodiments, form A of compound 1 has at least seven properties selected from the properties listed in paragraphs. from (a) to (l). In some embodiments, form A of compound 1 has at least eight properties selected from those listed in paragraphs. from (a) to (l). In some embodiments, form A of compound 1 has at least nine properties selected from those listed in paragraphs. from (a) to (l). In some embodiments, form A of compound 1 has at least ten properties selected from those listed in paragraphs. from (a) to (l). In some embodiments, form A of compound 1 is characterized by the properties listed in paragraphs. from (a) to (l).

In some embodiments, the powder x-ray pattern (XRPD) of Form A is substantially the same as the x-ray powder pattern shown in FIG. 1. In some embodiments, the XRPD Form A has characteristic peaks at 2-θ angles of 5.7±0.1°, 13.6±0.1°, 16.1±0.1°, 18.9±0.1°, 21.3±0.1°, and 21.6± 0.1°. In some embodiments, the x-ray powder diffraction pattern (XRPD) of Form A remains substantially the same after storage at 40° C. and 75% relative humidity (RH) for at least a week. In some embodiments, the x-ray powder diffraction pattern (XRPD) of crystalline form A remains essentially the same after storage at 25° C. and 97% relative humidity (RH) for at least a week.

In some embodiments, the IR (IR) spectrum of Form A is essentially the same as the IR spectrum shown in FIG. 2. According to some variants in the IR (IR) spectrum of Form A there are weak bands with a frequency of about 1584 cm ^-1 , about 1240 cm ^-1 , about 1147 cm ^-1 , about 1134 cm ^-1 , about 1099 cm ^-1 and about 1067 cm ^-1 .

In some embodiments, the Form A DSC thermogram is substantially the same as the DSC thermogram shown in FIG. 3. In some embodiments, the thermogravimetric (TGA) curve (thermogram) of Form A is substantially similar to the TGA thermogram shown in FIG. 4. In some embodiments, the DSC thermogram of Form A exhibits an endothermic effect starting at about 154°C, with a peak (maximum) at about 157°C, and an exothermic effect at about 159°C.

In some embodiments, Form A is non-hygroscopic.

According to some variants, the experimental value of the solubility of Form A in water is

- 21 040198 about 0.013 mg/ml at pH about 8.

In some embodiments, form A is prepared (crystallized) from ethyl acetate, isopropyl acetate, tetrahydrofuran, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), nitromethane, methanol, ethanol, acetonitrile, dioxane, methyl t-butyl ether (MTBE), anisole, acetone, heptanes, methanol/water mixtures or acetone/heptane mixtures.

In some embodiments, Form A is unsolvated. In some embodiments, form A is anhydrous.

Compound 1, form B.

In some embodiments, compound 1 is crystalline (has a crystalline structure). In some embodiments, compound 1 is a compound of crystalline form B. Crystalline form B of compound 1 has at least one of the following properties:

(a) X-ray powder diffraction pattern (XRPD) substantially the same as the X-ray powder diffraction pattern shown in FIG. 5;

(b) X-ray powder diffraction (XRPD) with characteristic peaks at 2-θ angles of 5.2±0.1°, 10.2±0.1°, 16.5±0.1°, 18.5±0.1°, and 20.8±0.1°;

(c) X-ray powder diffraction (XRPD) substantially the same after storage at 40° C. and 75% relative humidity (RH) for at least a week;

(d) X-ray powder diffraction (XRPD) substantially the same after storage at 25° C. and 97% relative humidity (RH) for at least a week;

(e) The IR (IR) spectrum is essentially the same as the IR spectrum shown in FIG. 6;

(e) in the IR (IR) spectrum there are weak bands with a frequency of about 1586 cm ^-1 , about 1573 cm ^-1 , about 1562 cm ^-1 , about 1229 cm ^-1 , about 1141 cm ^- 1 , about 1103 cm ^-1 , about 1056 cm ^-1 and about 1033 cm ^-1 ;

(g) The DSC thermogram is essentially the same as the DSC thermogram shown in FIG. 7;

(h) thermogravimetric (TGA) curve (thermogram) is practically similar to the TGA thermogram shown in FIG. 8;

(i) DSC thermogram showing an endothermic effect starting at about 99-154°C and peaking at about 115-118°C;

(j) an experimental water solubility value of about 0.0096 mg/ml at a pH of about 7.42; or (k) combinations thereof.

In some embodiments, form B of compound 1 is characterized by at least two properties selected from those listed in paragraphs. from (a) to (k). In some embodiments, form B of compound 1 is characterized by at least three properties selected from those listed in paragraphs. from (a) to (k). In some embodiments, form B of compound 1 is characterized by at least four properties selected from those listed in paragraphs. from (a) to (k). In some embodiments, form B of compound 1 is characterized by at least five properties selected from those listed in paragraphs. from (a) to (k). In some embodiments, form B of compound 1 is characterized by at least six properties selected from those listed in paragraphs. from (a) to (k). In some embodiments, form B of compound 1 is characterized by at least seven properties selected from those listed in paragraphs. from (a) to (k). In some embodiments, form B of compound 1 is characterized by at least eight properties selected from those listed in paragraphs. from (a) to (k). In some embodiments, form B of compound 1 is characterized by at least nine properties selected from those listed in paragraphs. from (a) to (k). In some embodiments, form B of compound 1 is characterized by the properties listed in paragraphs. from (a) to (k).

In some embodiments, the powder x-ray pattern (XRPD) of Form B has substantially the same pattern as the x-ray powder pattern shown in FIG. 5. In some embodiments, the Form B XRPD has characteristic peaks at 2-θ angles of 5.2±0.1°, 10.2±0.1°, 16.5±0.1°, 18.5±0.1°, and 20.8±0.1°. In some embodiments, the powder x-ray diffraction pattern (XRPD) of Form B remains substantially the same after storage at 40° C. and 75% relative humidity (RH) for at least a week. In some embodiments, the powder x-ray diffraction pattern (XRPD) of Form B remains essentially the same after storage at 25° C. and 97% relative humidity (RH) for at least a week.

In some embodiments, the IR (IR) spectrum is substantially the same as the IR spectrum shown in FIG. 6. According to some variants in the IR (IR) spectrum of Form B, there are weak bands with a frequency of about 1586 cm ^-1 , about 1573 cm ^-1 , about 1562 cm ^-1 , about 1229 cm ^-1 , about 1141 cm ^-1 , about 1103 cm ^-1 , about 1056 cm ^-1 and about 1033 cm ^-1 .

In some embodiments, the Form B DSC thermogram is substantially the same as the DSC thermogram shown in FIG. 7. According to some options, the thermogravimetric (TGA) curve

- 22 040198 (thermogram) form B is practically similar to the TGA thermogram shown in FIG. 8. In some embodiments, the DSC thermogram of Form B shows an endothermic effect starting at about 99-106°C, with a peak (maximum) at about 115-118°C.

In some embodiments, the experimental solubility of form B in water is about 0.0096 mg/ml at a pH of about 7.42.

In some embodiments, form B was prepared (crystallized) from methanol and water.

In some embodiments, Form B is unsolvated. In some embodiments, Form B is anhydrous.

Compound 1, form C.

In some embodiments, compound 1 is crystalline (has a crystalline structure). In some embodiments, compound 1 is a compound of crystal form C. Crystal form C of compound 1 has at least one of the following properties:

(a) X-ray powder diffraction pattern (XRPD) substantially the same as the X-ray powder diffraction pattern shown in FIG. 9;

(b) X-ray powder diffraction (XRPD) with characteristic peaks at 2-θ angles of 7.0±0.1°, 14.0±0.1°, 15.7±0.1°, 18.2±0.1°, 19.1±0.1°, 19.5±0.1°, 20.3 ±0.1°, 22.1±0.1° and 22.9±0.1°;

(c) The DSC thermogram is essentially the same as the DSC thermogram shown in FIG. 10;

(d) thermogravimetric (TGA) curve (thermogram) is practically similar to the TGA thermogram shown in FIG. eleven;

(e) DSC thermogram showing an endothermic effect starting at about 134-135°C and peaking at about 137-139°C; or (e) combinations thereof.

In some embodiments, form C of compound 1 has at least two properties selected from those listed in paragraphs. from (a) to (e). In some embodiments, form C of compound 1 is characterized by at least three properties selected from those listed in paragraphs. from (a) to (e). In some embodiments, form C of compound 1 has at least four properties selected from those listed in paragraphs. from (a) to (e). In some embodiments, form C of compound 1 is characterized by the properties listed in paragraphs. from (a) to (e).

In some embodiments, the powder x-ray pattern (XRPD) of Form C has substantially the same pattern as the x-ray powder pattern shown in FIG. 9. In some embodiments, the Form C XRPD has characteristic peaks at 2-θ angles of 7.0±0.1°, 14.0±0.1°, 15.7±0.1°, 18.2±0.1°, 19.1±0.1°, 19.5± 0.1°, 20.3±0.1°, 22.1±0.1° and 22.9±0.1°.

In some embodiments, the Form C DSC thermogram is substantially the same as the DSC thermogram shown in FIG. 10. In some embodiments, the thermogravimetric (TGA) curve (thermogram) of Form C is substantially similar to the TGA thermogram shown in FIG. 11. In some embodiments, the DSC thermogram of Form C exhibits an endothermic effect starting at about 134-135°C, with a peak (maximum) at about 137-139°C.

In some embodiments, form C was obtained (crystallized) from methanol and water. In some embodiments, form C was obtained (crystallized) from methanol.

In some embodiments, Form C is unsolvated. In some embodiments, form C is anhydrous.

Compound 1 Form D.

In some embodiments, compound 1 is crystalline (has a crystalline structure). In some embodiments, compound 1 is a compound of crystalline form D. The crystalline form D of compound 1 has at least one of the following properties:

(a) X-ray powder diffraction pattern (XRPD) substantially the same as the X-ray powder diffraction pattern shown in FIG. 12;

(b) X-ray powder diffraction (XRPD) with characteristic peaks at 2-θ angles of 7.2±0.1°, 8.0±0.1°, 9.2±0.1°, 14.5±0.1°, 18.5±0.1°, 19.5±0.1°, 20.7 ±0.1°, 21.0±0.1°, 21.9±0.1° and 22.4±0.1°;

(c) thermogravimetric (TGA) curve (thermogram) is practically similar to the TGA thermogram shown in FIG. 13; or (e) combinations thereof.

In some embodiments, form D of compound 1 has at least two properties selected from those listed in paragraphs. from (a) to (c). In some embodiments, form D of compound 1 is characterized by the properties listed in paragraphs. (a), (b), and (c).

In some embodiments, the XRPD Form D has substantially

- 23 040198 same pattern as the X-ray powder diffraction shown in FIG. 12. In some embodiments, the powder X-ray diffraction pattern (XRPD) of crystalline Form D has characteristic peaks at 2-θ angles of 7.2±0.1°, 8.0±0.1°, 9.2±0.1°, 14.5±0.1°, 18.5±0.1°, 19.5 ±0.1°,

20.7±0.1°, 21.0±0.1°, 21.9±0.1° and 22.4±0.1°.

In some embodiments, the thermogravimetric (TGA) curve (thermogram) of Form D is substantially the same as the TGA thermogram shown in FIG. 13.

In some embodiments, form D was prepared (crystallized) from methyl isobutyl ketone (MIBK). In some embodiments, form D is solvated. In some embodiments, form D is solvated with methyl isobutyl ketone.

Compound 1, form E.

In some embodiments, compound 1 is crystalline (has a crystalline structure). In some embodiments, compound 1 is a compound of crystalline form E. The crystalline form E of compound 1 has at least one of the following properties:

(a) an X-ray powder diffraction pattern (XRPD) substantially the same as the X-ray powder diffraction pattern shown in FIG. 14;

(b) X-ray powder diffraction (XRPD) with characteristic peaks at 2-θ angles of 7.8±0.1°, 8.8±0.1°, 16.1±0.1°, 18.1±0.1°, 19.3±0.1°, 19.5±0.1°, 20.5 ±0.1°, 21.6±0.1° AND 25.2±0.1°;

(c) The DSC thermogram is essentially the same as the DSC thermogram shown in FIG. 15;

(d) thermogravimetric (TGA) curve (thermogram) is practically similar to the TGA thermogram shown in FIG. 15; or (e) combinations thereof.

In some embodiments, Compound 1 Form E is characterized by at least two properties selected from those listed in paragraphs. from (a) to (d). In some embodiments, Compound 1 Form E is characterized by at least three properties selected from those listed in paragraphs. from (a) to (d). In some embodiments, form E of compound 1 has the properties listed in paragraphs. from (a) to (d).

In some embodiments, the XRPD Form E has substantially the same pattern as the XRPD shown in FIG. 14. In some embodiments, the Form E XRPD has characteristic peaks at 2-θ angles of 7.8±0.1°, 8.8±0.1°, 16.1±0.1°, 18.1±0.1°, 19.3±0.1°, 19.5± 0.1°, 20.5±0.1°, 21.6±0.1° and 25.2±0.1°.

In some embodiments, the Form E DSC thermogram is substantially the same as the DSC thermogram shown in FIG. 15. In some embodiments, the thermogravimetric (TGA) curve (thermogram) of Form E is substantially similar to the TGA thermogram shown in FIG. 15.

In some embodiments, Form E was prepared (crystallized) from toluene.

In some embodiments, form E is solvated. In some embodiments, form E is solvated with toluene.

Compound 1 Form F.

In some embodiments, compound 1 is crystalline (has a crystalline structure). In some embodiments, compound 1 is a compound of crystalline form F. The crystalline form F of compound 1 has at least one of the following properties:

(a) an X-ray powder diffraction pattern (XRPD) substantially the same as the X-ray powder diffraction pattern shown in FIG. 16;

(b) X-ray powder diffraction (XRPD) with characteristic peaks at 2-θ angles of 6.2±0.1°, 10.1±0.1°, 17.6±0.1°, 18.6±0.1°, 20.0±0.1°, 20.4±0.1°, 20.7 ±0.1°, 22.4±0.1°, 23.0±0.1°, 23.2±0.1°, 24.4±0.1°, 25.1±0.1°, 27.6±0.1°, 29.3±0.1° and 29.7±0.1°;

(c) the unit cell parameters are almost equal to the parameters given below at 100(2) K

- 24 040198

Crystal system Triclinic space group P1 A 9.6332(3) A A 105.762(3)° b 9.7536(4) A β 95.132(2)° With 15.0592(4)A At 111.332(3)° V 1240.15(7) A ³ Z 1 Density (calculated) 1.308 Mg/ ^m3 Absorption coefficient 0.726 mm1 Wavelength 1.54178 A F(000) 518

or (d) combinations thereof.

In some embodiments, form F of compound 1 has at least two properties selected from those listed in paragraphs. from (a) to (c). In some embodiments, Form F of Compound 1 is characterized by the properties listed in paragraphs. (a), (b), and (c).

In some embodiments, the XRPD Form F has substantially the same pattern as the XRPD shown in FIG. 16. In some embodiments, the Form F XRPD has characteristic peaks at 2-θ angles of 6.2±0.1°, 10.1±0.1°, 17.6±0.1°, 18.6±0.1°, 20.0±0.1°, 20.4± 0.1°, 20.7±0.1°, 22.4±0.1°, 23.0±0.1°, 23.2±0.1°, 24.4±0.1°, 25.1±0.1°, 27.6±0.1°, 29.3±0.1° and 29.7±0.1°.

According to some options, the unit cell parameters of the crystalline form E are practically equal to the parameters below at 100 (2) K ______________________

Crystal system Triclinic space group P1 A 9.6332(3) A A 105.762(3)° b 9.7536(4) A β 95.132(2)° With 15.0592(4)A At 111.332(3)° V 1240.15(7) A ³ Z 1 Density (calculated) 1.308 Mg/ ^m3 Absorption coefficient 0.726 mm1 Wavelength 1.54178 A F(000) 518

In some embodiments, Form E was prepared (crystallized) from methanol.

In some embodiments, crystalline form F is solvated. In some embodiments, crystalline Form F is solvated with methanol.

Obtaining crystalline forms.

In some embodiments, the crystalline forms of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1Hn-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2 -en-1-it is obtained as described in the Examples section. It should be noted that the temperatures and other conditions of the reactions presented in this application may vary.

Applicable solvents.

Therapeutic agents that may be administered to a mammal, such as a human, should be prepared in accordance with the following regulatory guidelines. Such government-regulated guidelines are known as Good Manufacturing Practices (GMP) guidelines. The GMP guidelines specify acceptable levels of impurities contained in active therapeutic agents, such as residual solvent in the final product, for example. Preferred solvents are those that are suitable for use in GMP facilities and are consistent with industrial safety considerations. Solvent groups are defined, for example, at the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) in Impurities: Guidelines for Residual Solvents, Q3C( R3), (November 2005).

Solvents are divided into three classes. Class 1 solvents are toxic and are not recommended. As for class 2 solvents, their use in the preparation of a therapeutic agent should be limited. Class 3 solvents are low toxicity solvents with a reduced risk to human health. Data for class 3 solvents show that

- 25 040198 when studying the direct effects of the drug and in short-term studies, they are less toxic and show negative results in genotoxicity studies.

Class 1 solvents to be avoided include benzene; carbon tetrachloride;

1,2-dichloroethane; 1,1-dichloroethane and 1,1,1-trichloroethane.

Examples of Class 2 solvents include acetonitrile, chlorobenzene, chloroform, cyclohexane, 1,2dichloroethane, dichloromethane, 1,2-dimethoxyethane, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4dioxane, 2-ethoxyethanol, ethylene glycol, formamide, hexane , methanol, 2-methoxyethanol, methylbutylketone, methylcyclohexane, N-methylpyrrolidine, nitromethane, pyridine, sulfolane, tetralin, toluene, 1,1,2trichloroethane and xylene.

Class 3 solvents that have low toxicity include acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butyl methyl ether (MTBE), cumene, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid , heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, methyl isobutyl ketone, 2methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, and tetrahydrofuran.

Residual solvents in active pharmaceutical ingredients (active pharmaceutical ingredients (APIs, APIs, APIs)) are explained by the method of obtaining APIs.

In some cases, solvents cannot be completely removed by practical methods. Proper selection of a solvent for the synthesis of APIs can increase yield or determine characteristics such as crystal shape, purity, and solubility. Therefore, the solvent is the most important indicator in the synthesis process.

In some embodiments, compositions containing Compound 1 include an organic solvent(s). In some embodiments, compositions containing Compound 1 contain residual organic solvent(s). In some embodiments, the compositions containing compound 1 contain residual amounts of a class 3 organic solvent. In some embodiments, the organic solvent is a class 3 organic solvent. In some embodiments, the class 3 organic solvent is selected from the group consisting of acetic acid, acetone, anisole, 1-butanol , 2-butanol, butyl acetate, tert-butyl methyl ether, cumene, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, methyl isobutyl ketone, 2- methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate and tetrahydrofuran. In some embodiments, the Class 3 organic solvent is selected from ethyl acetate, isopropyl acetate, t-butyl methyl ether, heptane, isopropanol, and ethanol.

Some terms.

Unless otherwise indicated, all technical and scientific terms used in this application have the same meaning as known to a person skilled in the art to which the claimed subject matter of this invention relates.

It should be understood that the foregoing general description and the following detailed description are exemplary and for purposes of explanation only, and do not limit the scope of the present invention.

In this application, the use of the singular includes the plural, unless otherwise noted. It should be noted that the use of terms in the singular in the description and claims includes these terms in the plural, unless the context clearly implies otherwise. In this application, the use of the union or means and/or, unless otherwise indicated. In addition, the use of the term including, as well as other related terms such as include, includes, and included, is not intended to be limiting.

Section headings given in this application are given for convenience only and should not be construed as limiting the described subject matter. All documents or portions of documents referenced in this application, including but not limited to patents, patent applications, articles, books, textbooks and monographs, are hereby incorporated by reference in their entirety into this application for any purpose.

The term "acceptable" or "pharmaceutically acceptable" when applied to a drug, composition or ingredient as used herein means that does not permanently adversely affect the general health of the patient being treated or does not alter the biological activity or properties of the compound and is relatively non-toxic.

In this context, the term agonist refers to a compound whose presence results in the biological activity of a protein, the same as the biological activity due to the presence of a natural ligand for the protein, such as in the case of Btk.

As used herein, the term partial agonist refers to a compound whose presence results in a biological activity of a protein of the same type as the biological activity due to the presence of a natural ligand for the protein, but of lesser magnitude.

In this context, the term antagonist refers to a compound whose presence results in

- 26 040198 to reduce the biological activity of the protein. In some embodiments, the presence of the antagonist results in complete inhibition of the biological activity of the protein, such as in the case of Btk. In some embodiments, antagonist is an inhibitor.

As used herein, the term amelioration (alleviation) of the symptoms of a particular disease, disorder, or condition by the administration of a particular compound or pharmaceutical composition refers to any reduction in severity, delay in onset, slow progression, or reduction in duration, permanent or temporary, persistent or occasional, that can be explained or associate with the administration of the compound or composition.

The term bioavailability refers to the amount, expressed as weight percent of the dose of administered compounds of the present invention, such as compounds of formula (1), that is delivered to the general circulation of the animal or human being studied. The cumulative exposure (AUQ^.^)) of a drug after intravenous administration is usually defined as 100% bioavailability (F%). The term oral bioavailability refers to the extent to which compounds of the present invention, such as compounds of formula (1), are absorbed into the general circulation when the pharmaceutical composition is administered orally as compared to intravenous administration.

The expression plasma concentration, plasma concentration refers to the concentration of the compounds of formula (1) in the blood plasma of a subject. It is understood that the concentration of compounds of formula (1) may vary markedly from subject to subject due to variability in metabolism and/or possible interactions with other therapeutic agents. According to one embodiment of the present invention, the plasma concentration of the compounds of formula (1) may vary from subject to subject. Similarly, values such as maximum plasma concentration (C _max ) or time to reach maximum plasma concentration (T _max ) or total area under the plasma concentration versus time curve (AUQ( ₀ .^)). Because of this variability, the amount required to constitute a therapeutically effective amount of a compound of formula (1) may vary from subject to subject.

The term Bruton's tyrosine kinase as used herein refers to Homo sapiens Bruton's tyrosine kinase as described, for example, in US Pat. No. 6,326,469 (GenBank Accession No. NP_000052).

The term Bruton's tyrosine kinase homologue as used herein refers to orthologues of Bruton's tyrosine kinase, e.g., orthologues in mice (GenBank Accession No. AAB47246), dogs (GenBank Acession No. XP_549139), rats (GenBank Acession No. NP_001007799), chickens ( GenBank Accession No. NP_989564) or striped pepper (GenBank Accession No. XP_698117), and fusion proteins of any of the above orthologs that exhibit tyrosine kinase activity against one or more Bruton's tyrosine kinase substrates (e.g., a peptide substrate containing the amino acid sequence AVLESEEELYSSARQ) .

It is intended that the terms co-introduction (use), etc. in this context encompasses the administration of selected therapeutic agents to a single patient and includes treatment regimens in which the agents are administered by the same or different routes of administration, either at the same or at different times.

The terms effective amount or therapeutically effective amount as used herein refer to a sufficient amount of an agent or compound administered that alleviates to some extent one or more symptoms of the disease or condition being treated. The result may be a reduction or amelioration of manifestations, symptoms, or any other desirable change in the biological system. For example, a therapeutically effective amount means the amount of a composition containing a compound of the invention necessary to provide a clinically significant reduction (alleviation) of disease symptoms without undue side effects. The appropriate effective amount in each individual case can be determined by methods such as a dose escalation study. The term therapeutically effective amount includes, for example, a prophylactically effective amount. An effective amount of a compound of the present invention means an amount effective to achieve the desired pharmacological effect or therapeutic benefit without undue side effects. It is understood that an effective amount or a therapeutically effective amount may vary from subject to subject, depending on changes in the metabolism of the compound of formula (1), age, weight, general condition of the subject being treated, the severity of the disease being treated, and the opinion of the attending physician. For example, a therapeutically effective amount can be determined by standard experimentation, including but not limited to dose escalation clinical trials.

The terms enhance or amplify means to increase or prolong either the activity or the duration of the desired effect. For example, enhancing the effect of therapeutic substances refers to the ability to increase or prolong either the activity or duration of action of therapeutic substances in the treatment of a disease, disorder, or pathological condition. The expression "amount effective to enhance" in this context refers to an amount adequate to enhance the effect of a therapeutic agent in the treatment of a disease, disorder or condition. When applied to a patient, amounts effective for this use will depend upon the severity and course of the disease, disorder or condition, prior treatment, the patient's medical condition and drug response, and the judgment of the attending physician.

The term homologous cysteine as used herein refers to a cysteine residue located at a position in the sequence that is homologous to the cysteine residue at position 481 of Bruton's tyrosine kinase as described herein. For example, cysteine 482 is a cysteine homologous to the cysteine of the rat Bruton tyrosine kinase orthologue, tyrosine 479 is homologous to the cysteine of the chicken Bruton tyrosine kinase orthologue, and cysteine 481 is homologous to the cysteine of the Bruton tyrosine kinase orthologue of striped pepper. In another example, the homologous cysteine of TXK, a member of the Tec family of kinases closely related to Bruton's tyrosine, is Cys 350. See also tyrosine kinase (TK) sequence alignments published at kinase.com/human/kinome/phylogeny.html.

The term identical in this context refers to two or more identical sequences or subsequences. In addition, the term substantially (substantially) identical in this context refers to two or more sequences that have a certain percentage of the same consecutive units when compared and aligned to the maximum match in the comparison window or in a certain area as determined by comparison algorithms or manual alignment and visual inspection. For example, two or more sequences may be substantially identical if the successive units are about 60% identical, about 65% identical, about 70% identical, about 75% identical, about 80% identical, about 85% identical, about 90% identical or about 95% identical in a particular area. Sequence identity can be observed over a length of at least 75-100 consecutive links, over a length of about 50 consecutive links, or, where the number of links is not indicated, over the entire length of the sequence. This definition also applies to a sequence that is complementary to the test sequence. For example, two or more polypeptide sequences are identical when the amino acid residues are the same, while two or more polypeptide sequences are substantially identical when the amino acid residues are about 60% identical, about 65% identical, about 70% identical, identical. about 75% identical, about 80% identical, about 85% identical, about 90% identical, or about 95% identical in a particular area. Identity can be observed in a region of at least 75-100 consecutive units, in a region of about 50 consecutive units, or, where the number of units is not indicated, throughout the length of the polypeptide sequence. Further, two or more polynucleotide sequences are identical when the nucleotide residues are the same, while two or more polynucleotide sequences are substantially identical when the nucleotide residues are about 60% identical, about 65% identical, about 70% identical, about 75% identical, about 80% identical, about 85% identical, about 90% identical, or about 95% identical in a particular area. Identity can be observed in a region of at least 75-100 consecutive units, in a region of about 50 consecutive units, or, where the number of units is not indicated, throughout the length of the polynucleotide sequence.

The terms inhibit, inhibit or inhibitor of the kinase in this context refers to the inhibition of the phosphotransferase activity of the enzyme.

The term irreversible inhibitor in this context refers to a compound that, upon contact with a target protein (e.g., a kinase), causes the formation of a new covalent bond with or within the protein, wherein one or more biological activities of the target protein (e.g., phosphotransferase activity) are reduced or abolished. regardless of the subsequent presence or absence of an irreversible inhibitor. In contrast, a reversible inhibitor, upon contact with a target protein, does not cause the formation of a new covalent bond with or within the protein and therefore can associate with the target protein and dissociate from the target protein.

The term irreversible Btk inhibitor as used herein refers to a Btk inhibitor that can form a covalent bond with a Btk amino acid residue. In one embodiment, an irreversible Btk inhibitor may form a covalent bond with a Cys residue in Btk; in specific embodiments, the irreversible inhibitor may form a covalent bond with a Btk Cys 481 residue or with a cysteine residue at the homologous corresponding position of another tyrosine kinase.

The term highlighted in this context refers to a separated corresponding component of interest that is separated from components of no interest. The isolated materials can be either in a dry or semi-dry state, or in the form of a solution, including, but not limited to, an aqueous solution. The isolated component may be in a homogeneous state, or the isolated component may be part of a pharmaceutical composition that contains additional pharmaceutically acceptable carriers and/or excipients. For example, nucleic acids

- 28 040198 or proteins are isolated when such nucleic acids or proteins do not contain at least some of the cellular components with which they are naturally associated, or when such nucleic acids are concentrated to at least a concentration higher than their concentration in an in vivo or in vitro product. Also, for example, a gene is isolated if it is separated from open reading frames that flank the gene and encode a protein other than that encoded by the target gene.

The term modulate in this context means to interact with a target, either directly or indirectly, in such a way as to change the activity of the target, including, for example, increase the activity of the target, inhibit the activity of the target, limit the activity of the target, or prolong the activity of the target.

The term modulator in this context refers to a compound that changes the activity of a molecule. For example, a modulator may increase or decrease the amount of a particular activity of a molecule compared to the amount of activity in the absence of the modulator. In some embodiments, a modulator means an inhibitor that reduces the magnitude of one or more activities of the molecule. In some embodiments, the inhibitor completely eliminates one or more activities of the molecule. In some embodiments, a modulator means an activator that increases the magnitude of at least one activity of the molecule. In some embodiments, no activity occurs in the absence of a modulator.

The term prophylactically effective amount as used herein refers to the amount of a composition administered to a patient who exhibits to a certain extent one or more symptoms of the disease, condition, or disorder being treated. When used prophylactically, such amounts may depend on the patient's health, weight, and the like. One skilled in the art would appreciate that such prophylactically effective amounts should be determined by routine experimentation, including, but not limited to, dose escalation clinical trials.

The term subject in this context refers to an animal that is the object of treatment, observation or experiment. For example, the subject may be, but is not limited to, a mammal, including but not limited to a human.

In this context, the term target activity refers to a biological activity that can be modulated by a selective modulator. Some examples of targeted activity include, but are not limited to, binding affinity, signal transduction, enzymatic activity, tumor growth, inflammatory or inflammation-related processes, and amelioration of one or more symptoms associated with a disease or condition.

As used herein, the term target protein, target protein, refers to a molecule or fragment of a protein molecule capable of being bound selectively by a binding compound. In some embodiments, the target protein is Btk.

As used herein, the terms treat, cure, or therapy include alleviating, alleviating, or ameliorating symptoms of a disease or condition, preventing additional symptoms, reducing or preventing the metabolic underlying cause of symptoms, inhibiting a disease or condition, such as arresting the progression of a disease or condition, alleviating a disease or condition, the ability to cause regression of a disease or condition, alleviation of a condition caused by a disease or disorder, or cessation of symptoms of a disease or pathological condition. The terms treat, treatment, or therapy include, but are not limited to, prophylactic and/or therapeutic treatment.

As used herein, _IC50 refers to the amount, concentration, or dose of a particular test compound that achieves 50% inhibition of a maximal response, such as Btk inhibition, in an assay that quantifies that response.

In this context, EC ₅₀ refers to the dose, concentration, or amount of a particular test compound that exhibits a dose-dependent effect equal to 50% of the maximum manifestation of a particular response that is caused, provoked or enhanced by a particular test compound.

Pharmaceutical composition/drugs.

Pharmaceutical compositions can be prepared in the usual way using one or more pharmaceutically acceptable carriers, including excipients and excipients that facilitate the preparation of active compounds for pharmaceutical use. The appropriate dosage form depends on the chosen method (route) of administration. Any of the well-known methods, carriers and excipients can be used as is customary in the art. Brief descriptions of the pharmaceutical compositions described in this application can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh

- 29 040198

Ed. (Lippincott Williams & Wilkins 1999), which are hereby incorporated by reference in their entirety.

The term pharmaceutical composition as used in this application refers to a mixture of a compound of formula 1 with other chemical components such as carriers, stabilizers, excipients, dispersing agents, suspending agents, thickening agents and/or excipients. The pharmaceutical composition facilitates the administration of a compound of the invention to a mammal. In carrying out the methods of treatment or use described in this application, a therapeutically effective amount of a compound of formula 1 is administered as part of a pharmaceutical composition to a mammal that has a disease, disorder or condition to be treated. Preferably the mammal is a human. The therapeutically effective amount may vary widely depending on the severity of the disease, the age and health of the subject, the activity of the compound used, and other factors. The compounds may be used alone or in combination with one or more therapeutic agents as components of a mixture.

The term "pharmaceutical combination" as used in this application means a product that results from mixing or combining more than one active ingredient and includes both fixed and non-fixed combinations of active ingredients.

The term fixed combination means that the active ingredients, for example, the compound of Formula 1 and the co-administered agent are both administered to the patient at the same time in the form of a single serving or dose. The term non-fixed combination means that the active ingredients, for example, the compound of formula 1 and the co-administered agent, are administered to the patient in separate portions or simultaneously, in parallel or sequentially at non-fixed time intervals, while such administration provides effective levels of the two compounds in the patient's body. This also applies to the use of cocktails, for example, the administration of three or more active ingredients.

In accordance with some embodiments of the invention, when preparing solid oral dosage forms, a crystalline compound of formula 1 is introduced into pharmaceutical compositions. In other embodiments, a crystalline compound of formula 1 is used to prepare pharmaceutical compositions other than oral solid dosage forms.

The pharmaceutical preparations of this invention may be administered to a subject by a variety of routes, including, but not limited to, oral, parenteral (eg, intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal routes of administration. Pharmaceutical preparations of the present invention include, but are not limited to, aqueous dispersions (water-based dispersions), self-emulsifying dispersions, solid solutions, liposome dispersions (liposomal dispersions), aerosols, solid dosage forms, powders, instant release preparations, controlled release preparations , fusible (fast melting) preparations, tablets, capsules, pills, delayed release preparations, extended release preparations, pulsed release preparations, preparations from many single particles and mixed preparations with immediate and controlled release.

Pharmaceutical compositions comprising a compound of the present invention can be prepared in a conventional manner, such as, for example, conventional mixing, dissolving, granulating, drageeing, elutriating, emulsifying, encapsulating, trapping, or compressing methods.

medicinal forms.

The compositions of the present invention can be formulated for administration to a subject by any conventional route, including, but not limited to, oral, parenteral (eg, intravenous, subcutaneous, or intramuscular), buccal, intranasal, rectal, or transdermal routes of administration. As used herein, the term subject is used to refer to an animal, preferably a mammal, including a human and a non-human mammal. The terms patient and subject may be used interchangeably.

Further, pharmaceutical compositions of the present invention which include a compound of formula (1) may be formulated into any suitable dosage form including, but not limited to, aqueous dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, and the like, for oral administration by the patient under treatment, solid dosage forms, controlled release preparations, fusible preparations, effervescent preparations, lyophilized preparations, tablets, powders, pills, dragees, capsules, delayed release preparations, extended release preparations, pulsatile release preparations , multiparticulate formulations, and instant and controlled release mixed formulations.

Pharmaceutical preparations for oral use can be prepared by mixing one or more solid excipients with one or more compounds of the present invention, optionally grinding the resulting mixture, and processing the mixture of granules, after adding, if necessary, appropriate excipients to obtain tablets or cores ( nuclei) dragee. Suitable excipients include, for example, fillers such as sugars including lactose, sucrose, mannitol or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or other substances such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. Disintegrators, grinding aids such as cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate can be added if necessary.

Pharmaceutical preparations that can be taken orally include hard gelatin capsules, as well as soft, sealed capsules made from gelatin and a plasticizer such as glycerin or sorbitol. Hard capsules may contain the active ingredients in admixture with excipients such as lactose, binders such as starches and/or lubricants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable solvents such as fixed (non-volatile) oils, liquid paraffin or liquid polyethylene glycol. In addition, stabilizers can be added. All preparations for oral use should be in dosage form suitable for such use.

In some embodiments, the solid dosage forms disclosed herein may be in the form of tablets (including a suspendable tablet, a low-melting (fast-melting) tablet, a tooth-disintegrating tablet, a fast-disintegrating tablet, an effervescent tablet, or a caplet), a pill, a powder (including sterile powder, single dose powder or effervescent powder), capsules (including both soft and hard capsules, e.g. solution, biodegradable dosage form, controlled release formulations, pulsatile release dosage forms (pulsed), multiparticulate dosage forms, pellets, granules or aerosol. In other embodiments, the pharmaceutical formulation is in powder form. In other embodiments, the pharmaceutical preparation is in the form of a tablet, including, but not limited to, a low melting tablet. In addition, the pharmaceutical preparations of the present invention may be administered as a single capsule or as multiple encapsulated dosage forms. In some embodiments, the pharmaceutical preparation is administered as two, three, or four capsules or tablets.

In some embodiments, solid dosage forms, such as tablets, effervescent tablets, and capsules, are prepared by mixing particles of a compound of formula (1) with one or more pharmaceutical excipients to form a dry mix (bulk mix) composition. When these dry mixes are said to be homogeneous, this means that the particles of the compound of formula (1) are evenly distributed throughout the composition so that the composition can be easily divided into single dosage forms with the same efficiency, such as tablets, pills and capsules. Individual single doses may also have a film coating that breaks down when swallowed or on contact with a diluent. These preparations can be prepared by conventional pharmacological methods.

Conventional pharmacological methods include, for example, one method or a combination of methods: (1) dry mixing, (2) direct compression, (3) grinding, (4) dry or non-aqueous granulation, (5) aqueous granulation, and (6) fusion. See, for example, Lachman et al., The Theory and Practice of Industrial Pharmacy (1986). Other methods include, for example, spray drying, panning, melt granulation, drying or fluid bed coating (e.g., Wurster coating), tangential (surface) coating, surface spraying, tableting, extrusion, and the like.

Solid pharmaceutical dosage forms of the present invention may include a compound of the present invention and one or more pharmaceutically acceptable additives such as a compatible carrier, binder, bulking agent, suspending agent, flavoring agent (flavoring agent), sweetener, disintegrating agent (disintegrant), dispersing agent, surfactant, lubricant, colorant, filler, solubilizer, wetting agent, plasticizer, stabilizer, absorption enhancer, wetting agent, antifoam agent, antioxidant, preservative, or one or more combinations thereof. In other aspects, a film coating is provided for a formulation of a compound of formula (1) obtainable by standard coating techniques, such as those described in Remington's Pharmaceutical Sciences, ^20th Edition (2000). In one embodiment, some or all of the particles of the compound of formula (1) are coated. In another embodiment, some or all of the particles of the compound of formula (1) are microencapsulated. In yet another embodiment, the particles of the compound of formula (1) are neither microencapsulated nor coated.

Suitable carriers for use in solid dosage forms of the present invention

- 31 040198 include, but are not limited to, gum arabic, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerin, magnesium silicate, sodium caseinate, soy lecithin, sodium chloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyl lactylate, carrageenan, monoglyceride, diglyceride, pregelatinized (pregelatinized) starch, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate stearate, sucrose, microcrystalline cellulose, lactose, mannitol, and the like.

Suitable excipients for use in the solid dosage forms of the present invention include, but are not limited to, lactose, calcium carbonate, calcium phosphate, dicalcium orthophosphate, calcium sulfate, microcrystalline cellulose, powdered cellulose, dextrose, dextrates, dextran, starches, pregelatinized starch, hydroxypropyl methyl cellulose (HPMC ), hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate stearate (HPMCAS), sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.

In order to release the compound of formula (1) from the solid matrix of the dosage form as efficiently as possible, disintegrants (disintegrators) are often used in the preparation, especially when the dosage forms are compressed with a binder. Disintegrators contribute to the destruction of the matrix of the dosage form due to swelling or capillary forces when moisture penetrates into the dosage form. Suitable disintegrants for use in the solid dosage forms of the present invention include, but are not limited to, natural starch such as corn starch or potato starch, pregelatinized starch such as National 1551 or Amijel®, or sodium carboxymethyl starch (sodium starch glycolate) such as Promogel® or Explotab®, cellulose such as wood pulp, microcrystalline cellulose such as Avicel®, Avicel® PH101, Avicel®PH102, Avicel® PH105, Elcema®P100, Emcocel®, Vivacel®, Ming Tia® and Solka-Floc® , methylcellulose, croscarmellose or crosslinked cellulose such as crosslinked sodium carboxymethylcellulose (Ac-Di-Sol®), crosslinked carboxymethylcellulose or crosslinked croscarmellose, crosslinked starch such as sodium carboxymethylstarch, crosslinked polymer such as crospovidone, crosslinked polyvinylpyrrolidone, alginate, such as alginic acid or salt of alginic acid such as sodium alginate, clay such as Veegum® HV (magnesium aluminum silicate gum, such as agar, guar gum, locust bean gum, karaya, pectin or tragacanth, sodium carboxymethyl starch, bentonite, natural sponge, surfactant, resin such as cation exchange resin, citrus pulp, sodium lauryl sulfate, sodium lauryl sulfate in combination with starch and the like.

In certain embodiments provided herein, the disintegrant is selected from the group consisting of natural starch, pregelatinized starch, sodium starch glycolate, crystalline methylcellulose, methylcellulose, croscarmellose sodium, crosslinked carboxymethylcellulose sodium, crosslinked carboxymethylcellulose, crosslinked croscarmellose, crosslinked starch such as sodium starch glycolate, a crosslinked polymer such as crospovidone, crosslinked polyvinylpyrrolidone, sodium alginate, clay or gum. In some embodiments described in this application, the disintegrant is croscarmellose sodium.

Binders impart cohesiveness to solid oral dosage form preparations: in the case of a powder-filled capsule preparation, they contribute to the formation of a block, a plug that can be placed in soft or hard shell capsules, or when used to prepare tablets, they ensure that the tablet will remain intact after compression and the mixture will be homogeneous before the compression or filling step. Materials suitable for use as binders in the solid dosage forms of the present invention include, but are not limited to, carboxymethylcellulose, methylcellulose (e.g., Methocel®), hydroxypropyl methylcellulose (e.g., Hypromellose USP Pharmacoat-603, acetate stearate hydroxypropylmethylcellulose (Aqoate HS-LF and HS), hydroxymethylcellulose, hydroxypropylcellulose (eg Klucel®), ethylcellulose (eg Ethocel®) and microcrystalline cellulose (eg Avicel®), microcrystalline dextrose, amylose , magnesium aluminum silicate, polysaccharides with acid groups; bentonites; gelatin; polyvinylpyrrolidone-vinyl acetate copolymer; crospovidone; povidone; starch; pregelatinized starch; tragacanth, dextrin, sugar such as sucrose (e.g. Dipac®), glucose, dextrose, molasses , mannitol, sorbitol, xylitol (such as Xylitab®), and lactose; natural or synthetic gum such as gum rabica (Acacia gum), gum tragacanth, gum ghatti, psyllium husk mucus, starch, polyvinylpyrrolidone (e.g. Povidone® CL, Kollidon® CL, polyplasdone® XL-10), larch arabinogalactan , veegum (Veegum®), polyethylene glycol, waxes, sodium alginate, etc.

As a rule, the amount of binder in powder-filled gelatin capsules of the drug is 20-70%. The amount of binder in tablets varies depending on whether direct compression, wet granulation, rolling, or whether other excipients such as excipients, which themselves can behave as mild binders, are used.

- 32 040198

Formulators can determine the amount of binder in formulations, but use of up to 70% binder in tablets is common.

Lubricants or glidants (glidants) (flow regulators) suitable for use in the solid dosage forms of the present invention include, but are not limited to, stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, alkali and alkaline earth metal salts such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearate, magnesium stearate, zinc stearate, waxes, Stearowet®, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, polyethylene glycol or methoxy polyethylene glycol, such as Carbovacs™, PEG 4000, PEG 5000, PEG 6000, propylene glycol, sodium oleate, glyceryl behenate, glyceryl palmitostearate, magnesium or sodium lauryl sulfate, etc.

In accordance with some options provided in this application, the lubricant is selected from the group consisting of stearic acid, calcium hydroxide, talc, corn starch, sodium salt of stearyl fumarate, stearic acid, sodium stearates, magnesium stearate, zinc stearate and waxes. In some embodiments of this invention, the lubricant is magnesium stearate.

Suitable excipients for use in the solid dosage forms of the present invention include, but are not limited to, sugars (including lactose, sucrose, dextrose), polysaccharides (including dextrates and maltodextrin), polyols (including mannitol, xylitol, and sorbitol), cyclodextrins, and the like. .P. In accordance with some options provided in this application, the filler is selected from the group consisting of lactose, sucrose, dextrose, dextrates, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrins, calcium phosphate, calcium sulfate, starches, modified starches, microcrystalline cellulose, microcellulose and talc. In some embodiments of this invention, the filler is microcrystalline cellulose.

The term water-insoluble excipient means compounds commonly used in pharmaceutical preparations such as calcium phosphate, calcium sulfate, starches, modified starches and microcrystalline cellulose and microcellulose (for example, having a density of about 0.45 g/cm ³ , for example, Avicel (Avicel), powdered cellulose) and talc.

Wetting agents suitable for use in the solid dosage forms of the present invention include, for example, oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, quaternary ammonium compounds (e.g., Polyquat 10®)), sodium oleate, sodium lauryl sulfate, magnesium stearate, sodium docusate, triacetin, vitamin E TPGS, etc.

Surfactants suitable for use in the solid dosage forms of the present invention include, for example, sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, poloxamers, bile salts, glyceryl monostearate, ethylene oxide-propylene oxide copolymers, such as Pluronic ®) (BASF), etc.

In some embodiments of the invention, the surfactant is selected from the group consisting of sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, poloxamers, bile salts, glyceryl monostearate, and ethylene oxide-propylene oxide copolymers. According to some options provided in this application, the surfactant is a sodium salt of lauryl sulfate.

Suspending agents suitable for use in solid dosage forms of the present invention include, but are not limited to, polyvinylpyrrolidone, such as polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, polyethylene glycol, such as polyethylene glycol, which may have a molecular weight of from about 300 to about 6000, or from about 3350 to about 4000, or from about 7000 to about 5400, vinylpyrrolidone-vinyl acetate (S630), sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, polysorbate-80, hydroxyethylcellulose, sodium alginate, gums, such as gum tragacanth and arabic gum, guar gum, xanthans including xanthan gum, sugars, cellulose derivatives such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, polysorbate-80, sodium alginate, polyethoxylated sorbitan monolaurate, povidone, and the like.

Antioxidants suitable for use in the solid dosage forms of the present invention include, for example, butylated hydroxytoluene (BHT), sodium ascorbate, and tocopherol.

It should be appreciated that the additives used in the solid dosage forms of the present invention are largely repetitive. Therefore, the above additives should be taken as an example only, and not as a limitation of the types of additives that can be included in the solid dosage forms of the present invention. Those skilled in the art can readily determine the amounts of such additives depending on the specific properties desired.

According to other variants, one or more layers of the pharmaceutical preparation are plasticized (they have been given plasticity, flexibility). As a rule, the plasticizer is a solid or liquid substance with a high boiling point. Appropriate plasticizers can be added in an amount of from about 0.01 wt.% up to about 50 wt.% (wt./wt.) by weight of the coating composition. Plasticizers include, but are not limited to, diethyl phthalate, citric acid esters, polyethylene glycol, glycerin, acetylated glycerides, triacetin, polypropylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearin, stearate, and castor oil.

Compressed tablets are solid dosage forms obtained by compacting (compressing) a dry powder of the preparations described above. In various embodiments, compressed tablets intended to dissolve in the mouth include one or more flavoring agents. In other embodiments, the compressed tablets include a film around the finished compressed tablet. In some embodiments, the film coating may provide a delayed release of the compound of formula (I) from the formulation. In other embodiments, the film coating promotes patient compliance (treatment adherence) (eg, Opadry® coatings or sugar-based coatings). Film coatings comprising Opadry® typically comprise from about 1% to about 3% by weight of the tablet. In other embodiments, the compressed tablets contain one or more excipients.

A capsule can be prepared by placing, for example, a dry mixture (powder) of a preparation of a compound of formula (I) into a capsule. In some embodiments, the formulations (non-aqueous suspensions and solutions) are placed in a soft gelatin capsule. In other embodiments, the formulations are filled into standard gelatin capsules or non-gelatin capsules containing HPMC. In other embodiments, the formulation is placed in coated particle capsules, wherein the capsule may be swallowed whole or the capsule may be opened prior to eating and poured into the food. In some embodiments, the therapeutic dose is divided into multiple (eg, two, three, or four) capsules. In some embodiments, the full dose of the drug is delivered as a capsule.

In some embodiments, particles of a compound of formula (1) and one or more excipients are mixed and compressed into a mass, such as a tablet, that is hard enough to provide a pharmaceutical composition that substantially disintegrates in less than about 30 minutes, less than about 35 minutes, less than less than about 40 minutes, less than about 45 minutes, less than about 50 minutes, less than about 55 minutes, or less than about 60 minutes after oral administration, the drug is released into the body fluid in the gastrointestinal tract.

In another aspect, dosage forms may include microencapsulated preparations. In some embodiments, one or two other compatible materials are present in the microencapsulated material. Examples of materials include, but are not limited to, pH modifiers, disintegrants, antifoam agents, antioxidants, flavoring agents, and carriers such as binders, suspending agents, disintegrants (disintegrants), fillers, surfactants. , solubilizers, stabilizers, lubricants, wetting agents and fillers.

Materials useful for microencapsulation of the present invention include materials compatible with the compounds of formula (1), which provide sufficient isolation of the compounds of formula (1) from other incompatible excipients. Materials compatible with compounds of formula (1) are those that delay the release of compounds of formula (1) in vivo.

Typical microencapsulation materials useful for delaying the release of formulations containing compounds of the present invention include, but are not limited to, hydroxypropyl cellulose (HPC) ethers such as Klucel® or Nisso HPC, low substituted hydroxypropyl cellulose (L-HPC) ethers , Hydroxypropyl methylcellulose (HPMC) ethers such as Seppifilm-LC, Pharmacoat®, Metolose SR, Methocel®-E, Opadry YS, PrimaFlo, Benecel MP824 and Benecel MP843, methylcellulose polymers such as Methocel®-A, Aqoat hydroxypropyl methylcellulose acetate stearate (HF-LS, HF-LG, HF-MS) and Metolose®, ethyl cellulose (EC) and mixtures thereof such as E461, Ethocel®, Aqualon®-EC, Surelease®, polyvinyl alcohol (PVA) such as Opadry AMB , hydroxyethylcelluloses such as Natrosol®, carboxymethylcelluloses and carboxymethylcellulose (CMC) salts such as Aqualon®-CMC, polyvinyl alcohol-polyethylene glycol copolymers such as Kollicoat IR®, monoglycerides (Myverol), triglycerides erides (KLX), polyethylene glycols, modified food starch, acrylic polymers and mixtures of acrylic polymers with cellulose ethers such as Eudragit® EPO, Eudragit® L30D-55, Eudragit® FS 30D Eudragit® L100-55, Eudragit® L100, Eudragit® S100, Eudragit® RD100, Eudragit® E100, Eudragit® L12.5, Eudragit® S12.5, Eudragit® NE30D and Eudragit® NE 40D, cellulose acetate phthalate, sepifilms such as mixtures of HPMC and stearic acid, cyclodextrins and mixtures of these materials .

In other embodiments, plasticizers such as polyethylene glycols, such as PEG 300, PeG 400, PEG 600, PEG 1450, PEG 3350 and PEG 800, are included in the microencapsulation material,

- 34 040198 stearic acid, propylene glycol, oleic acid and triacetin. In other embodiments, the microencapsulation material useful for delayed release of pharmaceutical compositions is selected from the USP (United States Pharmacopeia) or National Formulary (NF). In other embodiments, the encapsulating material is Klucel. In other embodiments, the encapsulating material is methocel.

Microencapsulated compounds of formula (1) can be prepared by methods known to those skilled in the art. Such known methods include, for example, spray drying processes, swirl disc solvent spray tip processes, melt processes, spray cooling methods, fluidized bed processes, electrostatic deposition, centrifugal extrusion, rotary slurry separation, liquid-gas polymerization. or solid-gas, extrusion under pressure or spraying into the bath of the extract obtained by liquid extraction. In addition to these processes, several chemical methods can also be used, such as complex coacervation, solvent evaporation, polymer-polymer immiscibility, liquid interfacial polymerization, in situ polymerization, liquid phase drying, and liquid phase desolvation. In addition to these methods, rolling, extrusion followed by spheronization, coacervation or coating with nanoparticles can also be used.

In one embodiment, the particles of compounds of formula (1) are microencapsulated prior to preparation in one of the above forms. In yet another embodiment, some of the particles or the bulk of the particles are coated prior to formulation by standard methods, such as those described in Remington's Pharmaceutical Sciences, ^20th Edition (2000).

In other embodiments, solid dosage forms of the compounds of formula (1) are plasticized (coated) in one or more layers. For example, a plasticizer is a solid or liquid substance with a high boiling point. Suitable plasticizers can be added in an amount of from about 0.01% to about 50% by weight. (w/w) based on the composition of the coating. Plasticizers may include, but are not limited to, diethyl phthalate, citric acid esters, polyethylene glycol, glycerin, acetylated glycerides, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearol (stearyl stearate), stearates, and castor oil.

In other embodiments, a powder may be prepared comprising the compounds of formula (I) described herein and one or more pharmaceutically acceptable excipients and flavoring agents. Such a powder may be prepared, for example, by mixing the compounds and optional pharmaceutical excipients to form a bulk formulation. Additional options also include a suspending agent and/or a wetting agent. This composition is evenly divided into single unit dosage forms in a package and dosage forms in a multi-dose package.

Powders of dry fizzy drinks are also prepared in accordance with other embodiments of the present invention. Effervescent salts are used to distribute drugs in water for oral administration. The effervescent salts may be in the form of granules or coarse powders containing the therapeutic agent in a dry mixture, usually consisting of sodium bicarbonate, citric acid and/or tartaric acid. When salts in compositions are added to water, acids and bases react to release carbon dioxide, causing fizzing (bubbles).

Examples of effervescent salts include, for example, the following ingredients: sodium bicarbonate or a mixture of sodium bicarbonate and citric and tartaric acids, if these ingredients are suitable for pharmaceutical use and provide a pH value of 6.0 or higher.

According to some variants of the invention, the solid dosage forms described in this application can be obtained in the form of delayed-release oral dosage forms containing an enteric coating, i.e. in the form of an oral dosage form of the pharmaceutical composition described in this application, which uses an enteric coating to effect release in the small intestine of the gastrointestinal tract. The enteric-coated dosage form may be a compressed or molded or extruded tablet/form (coated or uncoated) containing granules, powder, granulate, microspheres or particles of the active ingredient and/or other components of the composition, which may or may not themselves contain coating. The enteric coated dosage form may also be a capsule (coated or uncoated) containing granules, microspheres or granules of a solid carrier or compositions, which themselves may or may not contain a coating.

The term delayed release as used in this application refers to a form of delivery where release can occur at some generally predictable location in the gastrointestinal tract, more distant from where it would occur if there were no delayed release. . In some embodiments, the delayed release is obtained upon application of the coating. This can be applied to any coating of sufficient thickness, such that the enteric coating does not dissolve in the gastrointestinal tract at a pH below about 5.0, but dissolves at a pH of about 5.0 and above. It is expected that any anionic polymer characterized by

- 35 040198 pH-dependent solubility profile, can be used to obtain an enteric coating in the implementation of the methods and preparation of the compositions described in this application to ensure delivery to the lower gastrointestinal tract. In some embodiments, the polymers described in this application are anionic polymers with carboxyl groups. In other embodiments, the polymers and compatible blends thereof include, but are not limited to, shellac, also referred to as natural lacquer, which is a refined product derived from insect tar. The shellac coating is soluble in the medium at pH >7; acrylic polymers. The properties and behavior of acrylic polymers (mainly their solubility in biological fluids) can vary depending on the degree and type of substitution. Examples of suitable acrylic polymers include methacrylic acid copolymers and ammonium methacrylate copolymers. The polymers of the Eudragit E, L, S, RL, RS and NE series (Rohm Pharma) are available as organic solvent solubilized aqueous dispersions or dry powders. The Eudragit RL, NE, and RS series polymers do not dissolve in the gastrointestinal tract, but are permeable and are primarily used for targeting the colon. Polymers of the Eudragit E series dissolve in the stomach. Polymers of the Eudragit L, L-30D and S series do not dissolve in the stomach and dissolve in the intestine; cellulose derivatives. Examples of suitable cellulose derivatives are ethyl cellulose, mixtures of partial cellulose acetate esters with phthalic anhydride. The behavior of these derivatives may vary depending on the degree and type of substitution. Cellulose acetate phthalate (CAP) dissolves at pH >6. Aquateric (FMC) is an aqueous system and a sprayable ATS pseudolatex with a particle size of <1 µm. Other ingredients in Aquateric include Pluronics, Tweens, and acetylated monoglycerides. Other suitable cellulose derivatives include cellulose acetate trimellitate (Eastman); methylcellulose (Pharmacoat, Methocel); hydroxypropyl methylcellulose phthalate (HPMCP); hydroxypropyl methylcellulose succinate (HPMCS); and hydroxypropyl methylcellulose acetate succinate (eg AQOAT (Shin Etsu)). The behavior of these derivatives may vary depending on the degree and type of substitution. For example, HPMCP grades HP-50, HP-55, HP-55S, HP-55F are suitable polymers. The behavior of these derivatives may vary depending on the degree and type of substitution. For example, suitable types of hydroxypropyl methylcellulose acetate succinate include, but are not limited to, ASLG (LF), which dissolves at pH 5.0, AS-MG (MF), which dissolves at pH 5.5, and AS-HG (HF), which dissolves at higher pH values. pH. These polymers are sold in the form of granules or in the form of fine powders to obtain aqueous dispersions; polyvinyl acetate phthalate (PVAP). PVAP dissolves at pH >5 and is much less permeable to water vapor and gastric fluids.

In some embodiments, the coating may and usually does contain a plasticizer and optionally other coating excipients such as colorants, talc and/or magnesium stearate, which are well known in the art. Suitable plasticizers include triethyl citrate (Citroflex 2), triacetin (glycerol triacetate), acetyl triethyl citrate (Citroflec A2), Carbowax 400 (polyethylene glycol 400), diethyl phthalate, tributyl citrate, acetylated monoglycerides, glycerin, fatty acid esters, propylene glycol, and dibutyl phthalate.

In particular, anionic acrylic polymers with carboxyl groups typically contain 10-25% by weight of a plasticizer, in particular dibutyl phthalate, polyethylene glycol, triethyl citrate and triacetin. Conventional methods such as spraying or panning are used for coating. The thickness of the coating should be sufficient to ensure the integrity of the oral dosage form until it reaches the desired delivery site in the gastrointestinal tract.

Colorants, detackifiers, surfactants, antifoams, lubricants (e.g. carnauba wax or PEG) may be added to the coating formulation other than plasticizers to solubilize or disperse the coating material and to improve the properties of the coating and coated product.

In other embodiments, the compounds described in this application are delivered using pulsatile dosage forms. A pulsatile dosage form is capable of generating one or more immediate release pulsations at predetermined times after a controlled latency period or at specific locations.

Many other types of controlled release systems are known to those skilled in the art that are suitable for use with the compounds described in this application. Examples of such delivery systems include, for example, systems based on polymers such as polylactic and polyglycolic acids, polyanhydrides, and polycaprolactone; porous matrices, polymer-free systems which are lipids, including sterols such as cholesterol, cholesterol fatty acid esters, or neutral fats such as mono-, di- and triglycerides; hydrogel release systems; silastic systems; peptide based systems; wax-based coatings, biodegradable dosage forms, compressed tablets with conventional binders, etc. See, for example, Liberman et al., Pharmaceutical Dosage Forms, 2 Ed., Vol. 1, pp. 209-214 (1990); Singh et al., Encyclopedia of Pharmaceutical Technology, ^2nd Ed., pp. 751-753 (2002); U.S. Patent Nos. 4327725, 4624848, 4968509, 5461140, 5456923, 5516527, 5622721, 5686105, 5700410, 5977175,

- 36 040198

6,465,014 and 6,932,983, each of these publications is incorporated herein by reference in its entirety.

In some embodiments, pharmaceutical formulations (compositions) are provided that include particles of the compounds of formula (1) described herein and at least one dispersing agent or suspending agent, for oral administration to a subject. The compositions may be in the form of powder and/or granules to form a suspension and after mixing them with water a substantially homogeneous suspension is obtained.

It should be appreciated that there is overlap between the additives listed above used in the aqueous dispersions or suspensions described herein, as a given additive is often classified differently by various practitioners in the art or is commonly used with any of several different functions. Thus, the additives listed above should be considered as examples and non-limiting types of additives that can be introduced into the compositions described in this application. The amounts of such additives can be readily determined by one of skill in the art according to the specific properties desired.

Methods of dosing and treatment regimens.

In some embodiments, the amount of a compound of Formula 1 administered to a mammal is between 300 mg/day and 1000 mg/day (including this upper limit). In some embodiments, the amount of a compound of Formula 1 administered to a mammal is between 420 mg/day and 840 mg/day (including this upper limit). In some embodiments, the amount of a compound of Formula 1 administered to a mammal is about 420 mg/day, about 560 mg/day, or about 840 mg/day. In some embodiments, the amount of a compound of Formula 1 administered to a mammal is 420 mg/day. In other embodiments, the amount of a compound of formula 1 administered to a mammal is 560 mg/day.

In some embodiments, the AUC0.24 value of the compound of formula 1 is from about 150 to about 3500 ng-h/ml. In some embodiments, the AUC ₀ _ ₂₄ value of the compound of formula 1 is from about 500 to about 1100 ng-h/ml. In some embodiments, a compound of formula 1 is administered orally. In some embodiments, the compound of Formula 1 is administered once a day, twice a day, or three times a day. In some embodiments, a compound of Formula 1 is administered daily. In some embodiments, a compound of formula 1 is administered once a day. In some embodiments, a compound of Formula 1 is used as a maintenance drug.

The compound of formula 1 may be used in the preparation of preparations for inhibiting Btk or its homologue, or for the treatment of diseases or conditions that are (at least partially) beneficial effect of inhibition of Btk or its homologue, including the treatment of a subject who has been diagnosed with a hematological malignancy .

In addition, a method of treating any of the diseases or conditions described herein in a subject in need of such treatment comprises administering to said subject pharmaceutical compositions containing a compound of Formula 1, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable N-oxide, a pharmaceutically acceptable an acceptable metabolite, a pharmaceutically acceptable prodrug, or a pharmaceutically acceptable solvate thereof, in a therapeutically effective amount.

Compositions containing a compound of Formula 1 may be administered for prophylactic, therapeutic, or maintenance therapy.

In some embodiments, compositions containing a compound of formula 1 are administered for therapeutic purposes (eg, administered to a subject who has been diagnosed with a hematologic malignancy). In some embodiments, compositions containing a compound of Formula 1 are administered for therapeutic purposes (eg, administered to a subject who is susceptible to or at risk of developing hematologic cancer). In some embodiments, compositions containing a compound of formula 1 are administered to a patient who is in remission or receiving maintenance therapy.

The amounts of a compound of formula 1 depend on the intended use (eg therapeutic, prophylactic or maintenance therapy).

The amounts of a compound of formula 1 depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and drug response, as well as the judgment of the attending physician.

One skilled in the art can determine such therapeutically effective amounts through routine experimentation known in the art (including, but not limited to, dose escalation clinical trials). In some embodiments, the amount of a compound of formula 1 administered to a mammal is from 300 mg/day to 1000 mg/day (including

- 37 040198 this upper limit). In some embodiments, the amount of a compound of Formula 1 administered to a mammal is between 420 mg/day and 840 mg/day (including this upper limit). In some embodiments, the amount of a compound of Formula 1 administered to a mammal is between 400 mg/day and 860 mg/day (including this upper limit). In some embodiments, the amount of a compound of formula 1 is about 360 mg/day. In some embodiments, the amount of a compound of formula 1 is about 420 mg/day. In some embodiments, the amount of a compound of Formula 1 is about 560 mg/day. In some embodiments, the amount of a compound of Formula 1 is about 840 mg/day. In some embodiments, the amount of a compound of Formula 1 administered to a mammal is from 2 mg/day to 13 mg/day (including this upper limit). In some embodiments, the amount of a compound of Formula 1 administered to a mammal is from 2.5 mg/day to 8 mg/day (including this upper limit). In some embodiments, the amount of a compound of Formula 1 administered to a mammal is from 2.5 mg/day to 6 mg/day (including this upper limit). In some embodiments, the amount of a compound of Formula 1 administered to a mammal is from 2.5 mg/day to 4 mg/day (including this upper limit). In some embodiments, the amount of a compound of formula 1 is about 2.5 mg/day. In some embodiments, the amount of a compound of Formula 1 is about 8 mg/day.

In some embodiments, the pharmaceutical compositions described herein include about 140 mg of a compound of formula 1. In some embodiments, the capsule formulation described in this application includes about 140 mg of a compound of formula 1. In some embodiments, two, three, four, or five capsules are administered daily. In some embodiments, three or four capsules are administered daily. In some embodiments, three capsules containing 140 mg of the compound are administered daily. In some embodiments, four capsules containing 140 mg of the compound are administered daily. In some embodiments, the capsules are administered once a day. In some embodiments, multiple capsules are administered once a day.

In some embodiments, a compound of Formula 1 is administered daily. In some embodiments, a compound of Formula 1 is administered every second day.

In some embodiments, a compound of formula 1 is administered once a day. In some embodiments, a compound of Formula 1 is administered twice daily. In some embodiments, a compound of formula 1 is administered three times a day. In some embodiments, a compound of formula 1 is administered four times a day.

In some embodiments, the compound of Formula 1 is administered until the disease progresses, unacceptable toxicity occurs, or depending on the condition of the patient. In some embodiments, a compound of formula 1 is administered daily until disease progression ceases, unacceptable toxicity occurs, or depending on the condition of the patient. In some embodiments, a compound of Formula 1 is administered every second day until disease progression stops, unacceptable toxicity occurs, or depending on the condition of the patient.

In the event that the patient's condition has improved, the administration of the compounds may be carried out continuously at the discretion of the physician; alternatively, the dose of the drug being administered may be temporarily reduced, or the administration may be temporarily stopped for a period of time (i.e., a drug holiday occurs). The length of these holidays may vary between 2 days and 1 year, including, for example, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days or 365 days. Dose reduction during drug holidays can be 10-100%, including, for example, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100%.

As soon as there is an improvement in the patient's condition, the previous dose is administered, if necessary. The dose or frequency of administration, or both, may then be reduced, depending on the symptoms, to a level at which amelioration of the disease or disorder is maintained. However, the patient may require intermittent long-term therapy if symptoms of the disease occur.

The amount of a given agent that will correspond to such a condition depends on factors such as the type of particular compound, the type of disease or condition, its severity, the weight of the subject or host in need of treatment, but, nevertheless, this amount can be determined by routine experimentation known in the art, according to the particular circumstances of the case, including, for example, the kind of specific agent administered, the route of administration, the condition being treated, and the kind of subject or host being treated. However, in general, doses used in adults are usually in the range of 0.025000 mg per day, or about 1-1500 mg per day.

This desired dose may be administered as a single dose or as divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, such as two, three, four or more dose portions per day.

- 38 040198

The pharmaceutical composition described in this application may be in the form of unit dosage forms suitable for single administration of precise doses. In such unit dosage forms, there is a proportion of the composition containing a suitable amount of one or more compounds. The unit dosage form may be contained in a package containing discrete amounts of the formulation. Non-limiting examples of such unit dosage forms are tablets or capsules and powders in vials and ampoules. Aqueous suspensions may be packaged in non-resealable single dose containers.

Alternatively, resealable containers containing multiple doses may be used. In this case, a preservative is usually added to the composition. For example, formulations for parenteral injection may also be in unit dosage form, which are contained in, but not limited to, ampoules or multi-dose containers, and contain an added preservative.

In some embodiments, each unit dosage form contains 140 mg of a compound of formula 1. In some embodiments, the subject receives one unit dosage form per day. In some embodiments, the subject receives two unit dosage forms per day. In some embodiments, the subject receives three unit dosage forms per day. In some embodiments, the subject receives four unit dosage forms per day.

The above limits are indicative as the number of variables considered in formulating a treatment regimen is large and significant deviations from these recommended values are not uncommon.

Such dosages may be varied depending on various variables, without being limited by the activity of the compound used, the type of disease or condition being treated, the method of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.

The toxicity of the compounds and the therapeutic efficacy of the applied regimens can be determined using standard pharmaceutical techniques in cell cultures or experimental animals, including, but not limited to, determination of LD ₅₀ (dose that is lethal to 50% of the population) and ED50 (dose that is therapeutic effective for 50% of the population).

The ratio of doses that give toxic and therapeutic effects is called the therapeutic index, which can be expressed as the ratio of LD ₅₀ to ED ₅₀ .

Compounds with high therapeutic indices are preferred.

Data obtained using cell cultures and animal studies can be used to determine the range of doses for humans. Doses of such compounds are preferably in the range of circulating concentrations that include the ED50 with minimal toxicity. Doses may vary depending on the dosage forms used and the method of administration.

Complex therapy.

In some instances, it is expedient to administer a compound of formula 1 in combination with another therapeutic agent.

According to one embodiment of the invention, when using the compositions and when implementing the methods described in this application, other therapeutic agents are also used, which are selected based on their specific utility in the treatment of a given condition. In general, in the compositions described in this application, and when implementing variants where complex therapy is used, it is not necessary to administer other agents in the same pharmaceutical composition, and these agents, due to their different physical and chemical properties, are administered in other ways. In one embodiment, administration is first carried out in accordance with established protocols and then, based on the observed effects, the route of administration and the time of administration are changed.

In various embodiments, the compounds are administered in parallel (eg, simultaneously, substantially simultaneously, or under the same treatment protocol) or sequentially, depending on the nature of the disease, the condition of the patient, and the type of compounds chosen. In some embodiments, the determination of the order of administration and the number of repetitions of the administration of each therapeutic agent during the implementation of the treatment protocol is based on an assessment of the course of the disease and the condition of the patient.

In the complex therapy described in this application, the doses of co-administered compounds depend on the type of drug used together, the type of drug used, the type of disease being treated, and other factors.

Individual compounds of such combinations are administered either sequentially or simultaneously as separate or combined pharmaceutical compositions. In one embodiment, the individual compounds are administered simultaneously as combined pharmaceutical compositions. Appropriate doses of known therapeutic agents are determined by those skilled in the art.

The combinations of therapeutic agents described in this application are usually used in the form of pharmaceutical compositions together with pharmaceutically acceptable diluent(s) or wear

- 39 040198 lem(s).

In some embodiments, there is provided a method of treating cancer in a subject in need thereof, comprising administering to the subject an amount of a compound of Formula 1. In some embodiments, such method comprises administering a second cancer treatment regimen.

In some embodiments, administration of a Btk inhibitor prior to the second cancer treatment regimen reduces the occurrence of immune-mediated responses to the drugs of the second treatment regimen. In some embodiments, administration of a compound of formula 1 prior to administration of ofatumumab reduces the occurrence of immune-mediated responses to the action of ofatumumab.

In some embodiments, the second cancer treatment regimen includes the use of a chemotherapeutic agent, a steroid, an immunotherapeutic agent, a targeted therapy, or a combination thereof.

In some embodiments, the second cancer treatment regimen comprises the use of an inhibitor of the B cell receptor signaling cascade. In some embodiments, such a B cell receptor signaling cascade inhibitor is a CD79A inhibitor, a CD79B inhibitor, a CD19 inhibitor, a Lyn inhibitor, a Syk inhibitor, a PI3K inhibitor, a Blnk inhibitor, a PLCy inhibitor, a PKCe inhibitor, or a combination thereof.

In some embodiments, the second cancer treatment regimen comprises an antibody, a B cell receptor signaling cascade inhibitor, a PI3K inhibitor, an IAP inhibitor, an mTOR inhibitor, a radioimmunotherapy agent, a DNA damaging agent, a proteasome inhibitor, a Cyp3A4 inhibitor, a histone deacetylase inhibitor, a protein kinase inhibitor. , a hedgehog protein inhibitor, an Hsp90 inhibitor, a telomerase inhibitor, a Jak1/2 inhibitor, a protease inhibitor, a PKC inhibitor, a PARP inhibitor, or a combination thereof.

In some embodiments, the second cancer treatment regimen uses chlorambucil, ifosfamide, doxorubicin, mesalazine, thalidomide, lenalidomide, temsirolimus, everolimus, fludarabine, fostamatinib, paclitaxel, docetaxel, ofatumumab, rituximab, dexamethasone, prednisone, CAL-101, ibritumomab, tositumumab, bortezomib , pentostatin, endostatin, or a combination thereof.

In some embodiments, the second cancer treatment regimen comprises cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone, and optionally rituximab.

In some embodiments, the second cancer treatment regimen comprises bendamustine and rituximab.

In some embodiments, the second cancer treatment regimen comprises fludarabine, cyclophosphamide, and rituximab.

In some embodiments, the second cancer treatment regimen comprises cyclophosphamide, vincristine, and optionally rituximab.

In some embodiments, the second cancer treatment regimen comprises etoposide, doxorubicin, vincristine, cyclophosphamide, prednisolone, and optionally rituximab.

In some embodiments, the second cancer treatment regimen comprises dexamethasone and lenalidomide.

In some embodiments, the second cancer treatment regimen comprises the use of a proteasome inhibitor. In some embodiments, the second cancer treatment regimen comprises bortezomib. In some embodiments, the second cancer treatment regimen comprises the use of epoxy ketone. In some embodiments, the second cancer treatment regimen comprises the use of epoxomycin. In some embodiments, the second cancer treatment regimen comprises the use of an epoxy ketone tetrapeptide. In some embodiments, the second cancer treatment regimen comprises carfilzomib. In some embodiments, the second cancer treatment regimen comprises disulfram, epigallocatechin-3-gallate, salinosporamide A, ONX 0912m CEP-18770, MLN9708, or MG132.

In some embodiments, the second cancer treatment regimen comprises the use of a Cyp3A4 inhibitor. In some embodiments, the second cancer treatment regimen comprises indinavir, nelfinavir, ritonavir, clarithromycin, itraconazole, ketoconazole, nefazodone. In some embodiments, the second cancer treatment regimen comprises the use of ketoconazole.

In some embodiments, the second cancer treatment regimen comprises the use of a Janus kinase (JAK) inhibitor. In some embodiments, the second cancer treatment regimen comprises lestaurtinib, tofacitinib, ruxolitinib, CYT387, baricitinib, or pacritinib.

In some embodiments, the second cancer treatment regimen comprises the use of a histone deacetylase inhibitor (HDAC inhibitor, HDI). In some embodiments, the second cancer treatment regimen comprises hydroxamic acid (or hydroxamate), including trichostatin A, vorinostat (SAHA), belinostat (PXD101), LAQ824, ipanobinostat (LBH589), a cyclic tripeptide such as trapoxin B, depsipeptide, benzamide such as entinostat (MS-40 040198

275), CI994 and mocetinostat (MGCD0103), an electrophilic ketone or aliphatic acid compound such as phenylbutyrate, and valproic acid.

Additional cancer treatment agents include chlormethines such as, for example, bendamustine, chlorambucil, chlormethine, cyclophosphamide, ifosfamide, melphalan, prednimustine, trofosfamide; alkylsulfonates such as busulfan, mannosulfan, treosulfan; ethyleneimines such as carboquone, thiotepa, triaziquone; nitrosoureas such as carmustine, fotemustine, lomustine, nimustine, ranimustine, semustine, streptozocin; epoxy compounds such as, for example, etoglucide; other alkylating agents such as, for example, dacarbazine, mitobronitol, pipobroman, temozolomide; folic acid analogues such as, for example, methotrexate, permetrexed, pralatrexate, raltitrexed; purine analogs such as, for example, cladribine, clofarabine, fludarabine, mercaptopurine, nelarabine, thioguanine; pyrimidine analogs such as, for example, azacitidine, capecitabine, carmofur, cytarabine, decitabine, fluorouracil, gemcitabine, tegafur; vinca alkaloids such as, for example, vinblastine, vincristine, vindesine, vinflunine, vinorelbine; podophyllotoxin derivatives such as, for example, etoposide, teniposide; colchicine derivatives such as, for example, demecolcin; taxanes such as, for example, docetaxel, paclitaxel, paclitaxel polyglumex; other plant alkaloids and natural products such as, for example, trabectedin; actinomycins such as, for example, dactinomycin; anthracyclines such as, for example, aclarubicin, daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, pyrarubicin, valrubicin, zorubicin; other cytotoxic antibiotics such as, for example, bleomycin, ixabepilone, mitomycin, plicamycin; platinum compounds such as, for example, carboplatin, cisplatin, oxaliplatin, satraplatin; methylhydrazines such as, for example, procarbazine; sensitizers such as, for example, aminolevulinic acid, efaproxiral, methylaminolevulinate, sodium porfimer, temoporfin; protein kinase inhibitors such as, for example, dasatinib, erlotinib, everolimus, gefitinib, imatinib, lapatinib, nilotinib, pazopanib, zorafenib, sunitinib, temsirolimus; other anti-neoplastic agents such as, for example, alitretinoin, altretamine, amsacrine, anagrelide, arsenic trioxide, asparaginase, bexarotene, bortezomib, celecoxib, denileukin diphlitox, estramustine, hydroxycarbamide, irinotecan, lonidamine, masoprocol, miltefosein, mitoguazan, pegasentotane, oblimer mitotane , pentostatin, romidepsin, sitimagen ceradenovec, thiazofurin, topotecan, tretinoin, vorinostat; estrogens, such as, for example, diethylstilbenol, ethinylestradiol, fosfestrol, polyestradiol phosphate; progestogens such as, for example, gestonorone, medroxyprogesterone, megestrol; gonadotropin-releasing hormone analogues such as, for example, buserelin, goserelin, leuprorelin, triptorelin; antiestrogen such as, for example, fulvestrant, tamoxifen, toremifene; antiandrogens such as, for example, bicalutomide, flutamide, nilutamide, enzyme inhibitors, aminoglutethimide, anastrozole, exemestane, formestane, letrozole, vorozol; other hormone antagonists such as, for example, abarelix, degarelix; immunostimulants such as, for example, histamine dihydrochloride, mifamurtide, pidotimod, plerixaphor, roquinimex, timopentin; immunosuppressants such as, for example, everolimus, husperimus, leflunomide, mycophenolic acid, sirolimus; calcineurin inhibitors such as, for example, cyclosporine, tacrolimus; other immunosuppressants such as, for example, azathioprine, lenalidomide, methotrexate, thalidomide; and radiopharmaceuticals such as, for example, yobenguan.

Additional cancer treatment agents include interferons, interleukins, tumor necrosis factors, growth factors, and the like.

Additional agents for the treatment of cancer include immunostimulatory agents such as, for example, ancestim, filgrastim, lenograstim, molgramostin, pegfilgrastim, sargramostin; interferons, such as, for example, interferon a, interferon a natural, interferon a-2a, interferon a-2b, interferon alfacon-1, interferon a-n1, interferon β natural, interferon b-1a, interferon e-1b, interferon γ , peginterferon a-2a, peginterferon a-2b; interleukins such as, for example, aldesleukin, oprelvekin; other immunostimulants such as, for example, BCG vaccine, glatiramer acetate, histamine dihydrochloride, immunocyanin, lentinan, melanoma vaccine, mifamurtide, pegademase, pidotimod, plexaphor, poly T:C, poly ICLC, roquinimex, tasonermin, timopentin; immunosuppressants such as, for example, abatasept, abetimus, alefacept, antilymphocyte immunoglobulin (equine), antithymocyte immunoglobulin (rabbit), eculizumab, efalizumab, everolimus, husperimus, leflunomide, muromab-CD3, mycophenolic acid, natalizumab, sirolimus; TNF alpha inhibitors such as, for example, adalimumab, afelimomab, sertolizumab pegol, etanercept, golimumab, infliximab; interleukin inhibitors such as, for example, anakinra, basiliximab, canakinumab, daclizumab, mepolizumab, rilonacept, tosilizumab, ustekinumab; calcineurin inhibitors such as, for example, cyclosporine, tacrolimus; other immunosuppressants such as, for example, azathioprine, lenalidomide, methotrexate, thalidomide.

Additional anticancer agents include adalimumab, alemtuzumab, basiliximab, bevasizumab, cetuximab, sertolizumab pegol, daclizumab, eculizumab, efalizumab, gemtuzumab, ibritumomab tiuxetan, infliximab, muromonab-CD3, natalizumab, panitumumab, ranibizumab, tuzimumab, or tuzimumab and their combinations.

- 41 040198

Additional anticancer agents include monoclonal antibodies such as, for example, alemtuzumab, bevacizumab, catumaxomab, cetuximab, edrecolomab, gemtuzumab, ofatumumab, panitumumab, rituximab, trastuchzumab, immunosuppressants, eculizumab, efalizumab, muromab-CD3, natalizumab; TNF-α inhibitors such as, for example, adalimumab, afelimomab, certolizumab pegol, golimumab, infliximab, interleukin inhibitors, basiliximab, canakinumab, daclizumab, mepolizumab, tosilizumab, ustekinumab, radiopharmaceutical agents, ibritumomab tiuxetan, tositumomab; other monoclonal antibodies such as e.g. , конатумумаб, дацетузумаб, деносумаб, экулизумаб, эпратузумаб, эртумаксомаб, этарацизумаб, фигитумумаб, фресолимумаб, галиксимаб, ганитумаб, гемтузумаба озогамицин, глембатумумаб, ибритумомаб, инотузумаба озогамицин, ипилимумаб, лексатумумаб, линтузумаб, лукатумумаб, мапатумумаб, матузумаб, милатузумаб, моноклональное антитело СС49 , necitumumab, nimotuzumab, ofatumumab, oregovomab, pertuzumab, ramakurimab, ranibizumab, ciplizumab, sonepcizumab, tanezumab, tositumumab, trastuzumab, tremelimumab, tucotuzumab celloleukin, veltuzumab, visilizumab, volociximab, zalutumumab.

Other anticancer agents include agents that affect the tumor microenvironment, such as the cell signaling chain (eg, phosphatidylinositol 3-kinase (PI3K) signaling cascade, B-cell receptor signal, and IgE receptor signal).

In some embodiments, the second agent is a PI3K inhibitor or a syc kinase inhibitor. In one embodiment, the syc kinase inhibitor is R788. In another embodiment, the agent is a PKCy inhibitor such as, for example, enzastaurin.

Examples of agents that act on the tumor microenvironment include a PI3K signal inhibitor, a syc kinase inhibitor, protein kinase inhibitors such as, for example, dasatinib, erlotinib, everolimus, gefitinib, imatinib, lapatinib, nilotinib, pazopanib, zorafenib, sunitinib, temsirolimus; other angiogenesis inhibitors such as, for example, GT-111, JI-101, R1530; other kinase inhibitors such as e.g. , BGJ398, BGT226, BI811283, BI6727, BIBF 1120, BIBW 2992, BMS-690154, BMS-777607, BMS-863233, BSK461364, CAL-101, CEP-11981, CYC116, DCC-2036, Enicyclibt, Enicyclibt, 07 EMD 1214063, ENMD-2076, динатриевую соль фостаматиниба, GSK2256098, GSK690693, INCB18424, INNO406, JNJ-26483327, JX-594, KX2-391, линифаниб, LY2603618, MGCD265, MK-0457, MK1496, MLN8054, MLN8237, MP470, NMS -1116354, NMS-1286937, ON O1919.Na, OSI-027, OSI-930, Btk Inhibitor, PF00562271, PF-02341066, PF-03814735, PF-04217903, PF-04554878, PF-04691502, PF-37 -739358, PLC3397, progenipoetin, R547, R763, ramucirumab, regorafenib, RO5185426, SAR103168, SCH 727965, SGI-1176, SGX523, SNS-314, TAK-593, TAK-901, TKI258, TLN-237, TTP1647 XL228, XL281RO5126766, XL418 and XL765.

Other examples of anticancer agents for use in combination with a Btk inhibitor include inhibitors of mitogen-activated protein kinase signals, eg U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006, wortmannin, or LY294002; Syk inhibitors; mTOR inhibitors; and antibodies (eg Rituxan).

Other examples of anticancer agents for use in combination with a Btk inhibitor include adriamycin, dactinomycin, bleomycin, vinblastine, cisplatin, acivicin; aclarubicin; acodazole hydrochloride; acronin; adoselin; aldesleukin; altretamine; ambomycin; amethantron acetate; aminoglutethimide; amsacrine; anastosol; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafida dimesylate; bizelesin; bleomycin sulfate; brekvinar sodium; bropyrimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; chlorambucil; siromycin; cladribine; crisnatol mesilate; cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin; desaguanine; desaguanine mesylate; diaziquon; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin; enpromat; epipropidin; epirubicin hydrochloride; erbulozol; esorubicin hydrochloride; estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozol hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; flurocitabine; fosquidon; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; imofosin; interleukin II (including recombinant interleukin II, or rIL2), interferon a-2a; interferon a-2b; interferon a-n1; interferon a-n3; interferon e-1a; interferon y-1b; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; loxantrone hydrochloride; mazoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; myenogaryl; mercaptopurine; methotrexate; methotrexate

- 42 040198 sodium; methoprine; meturedepu; mitindomide; mitocarcin; mitocromine; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxysuran; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perphosphamide; pipobroman; piposulfan; pyroxantrone hydrochloride; plicamycin; plomestan; porfimer sodium; porphyromycin; prednimustine; procarobazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprin; rogletimide; safingol; safingol hydrochloride; semustine; symtrazen; sodium sparphosate; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantrone hydrochloride; temporfin; teniposide; teroxirone; testolactone; thiamiprin; thioguanine; thiotepa; thiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulosole hydrochloride; chlormethine; uredepu; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; winepidine sulfate; vinglycinate sulfate; vieleurosin sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozol; zeniplatin; zinostatin; zorubicin hydrochloride.

Other anti-cancer agents that may be used in combination with a Btk inhibitor include: 20-epi-1, 25-dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adcipenol; adoselin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; G antagonist; antarelix; antidorsalizing morphogenetic protein-1; antiandrogen, antiestrogen; antineoplaston; antisense oligonucleotides; aficoline glycinate; modulators of apoptotic genes; apoptosis regulators; apuric acid; araCDP-DL-PTBA; arginine deaminase; azulacrine; atamestan; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; Azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ABL antagonists; benzochlorines; benzoyl-staurosporine; β-lactam derivatives; β-alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafid; bistratene A; bizelesin; breflat; bropyrimine; budotitan; butionine sulfoximine; calcipotriol; calfostin C; derivatives of camptothecin; canaripox IL-2; capecitabine; carboxamide aminotriazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorins; chlorquingoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomiphene analogues; clotrimazole; collismycin A; collismycin B; combrestatin A4; analogue of combrestatin; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine octophosphate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodemnin B; deslorelin; dexamethasone; dexiphosphamide; dexrazoxane; dexverapamil; diaziquon; didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; 9-dioxamycin; diphenylepyromustine; docosanol; dolasetron; doxyfluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosin; edrecolomab; eflornithine; element; emitfur; epirubicin; episteride; an estramustine analog; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastin; fluasterone; fludarabine; fluorodaunorubicin hydrochloride; forfenimeks; formestane; fostriecine; fotemustine; gadolinium texafirin; gallium nitrate; halocytabine; ganirelix; helitinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifen; idramantone; ylmofosin; ilomostat; imidazoacridones; imiquimod; immunostimulatory peptides; insulin, for example, a growth factor receptor-1 inhibitor; interferon agonists; interferons; interleukins; jobenguan; iododoxorubicin; ipomeanol, iroplakt; irsogladin; isobengazole; isogomogalichondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lpnreotide; leunamycin; lenograstim; lentinan sulfate; leptostatin; letrozole; leukemia inhibitory factor; leukocyte interferon alpha; leuprolide + estogen + progesterone; leuprorelin; levamisole; liarozol; analogue of linear polyamine; a lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricin; lometrexol; lonidamine; loxantrone; lovastatin; loxoribin; lurtothecan; lutetium texafirin; lysophyllin; lytic peptides; maytansine; mannostatin A; marimastat; mazoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaryl; merbaron; metererin; methioninase; metoclopramide; an MIF inhibitor; mifepristone; miltefosine; peaceful; double stranded mismatch RNA; mitoguazone; mitolactol; mitomycin analogues; mitonafid; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramming; monoclonal antibody, human chorionic gonadotropin; monophosphoryl lipid A+myobacteria cell wall sk; mopidamol; multiple drug resistance gene inhibitor; therapy based on the use of an oncosuppressor in many tumors; the anti-cancer agent mustargen; extract of cell walls of mycobacteria; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; pile; naloxone + pentazocine; napavin; nafterpine; nartograstim; nedaplatin; nemorubicin; nonridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrulline; 06-benzylguanine; octreotide;

- 43 040198 okicenon; oligonucleotides; onapriston; ondansetron; oracin; oral cytokine inducer; ormaplatin; osateron; oxaliplatin; oxaunomycin; palauamine; palmitoyl rhizoxin; pamidronic acid; panoxytriol; panomifen; parabactin; paselliptin; pegaspargase; peldesin; pentosan polysulfate sodium salt; pentostatin; pentrosol; perflubron; perphosphamide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pyrarubicin; pyrithrexim; placetin A; placetin B; a plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-triamine complex; porfimer sodium salt; porphyromycin; prednisone; propylbisacridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; a protein kinase C inhibitor; protein kinase C inhibitors; microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; conjugate of pyridoxylated hemoglobin with polyoxyethylene; raf antagonists; raltitrexed; ramosetron; farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; demethylated relleptin; rhenium etidronate Re 186; rhizoxin; ribozymes; retinamide RII; rogletimide; rogitukin; romurtide; rockwinimex; rubiginone B1; ruboxyl; safingol; sentopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; aging inhibitor 1; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen-binding protein; sisofiran; sobuzoxan; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparphosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem cell division inhibitors; stypiamide; stromelysin inhibitors; sulfinosin; an overactive vasoactive intestinal peptide antagonist; suradist; suramin; svensonin; synthetic glucosaminoglucans; thallimustin; tamoxifen metiodide; tauromustine; tazarotene; sodium salt of tecogalan; tegafur; tellurpyryllium; telomerase inhibitors; temporfin; temozolomide; teniposide; tetrachlorodecoxide; tetrazomin; taliblastin; thiocoralin; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid-stimulating hormone; etiopurine ethylol; tirapazamine; titanocene bichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; inhibitory growth factor of the urogenital sinus; urokinase receptor antagonists; vapreotide; variolin B; vector system; gene therapy using erythrocytes; velaresol; veramin; verdina; verteporfin; vinorelbine; vinxaltin; vitaxin; vorozol; zanoterone; zeniplatin; zilascorb and zinostatin stimalamer.

Other anti-cancer agents that may be used in combination with a Btk inhibitor include alkylating agents, antimetabolites, natural products or hormones such as chlormethines (eg mechlorethamine, cyclophosphamide, chlorambucil, etc.), alkyl sulfonates (eg busulfan), nitrosoureas (eg carmustine, lomustine, etc.), or triazenes (decarbazene, etc.). Examples of antimetabolites include, but are not limited to, folic acid analog (eg, methotrexate) or pyrimidine analogs (eg, cytarabine), purine analogs (eg, mercaptopurine, thioguanine, and pentostatin).

Examples of alkylating agents that can be used in combination with a Btk inhibitor include, but are not limited to, chlormethines (eg, mechlorethamine, cyclophosphamide, chlorambucil, melphalan, and the like), ethyleneimine, and methylmelamines (eg, hexamethylenemelamine, thiotepa), alkylsulfonates (eg busulfan), nitrosoureas (eg carmustine, lomustine, semustine, streptozocin, etc.), or triazenes (decarbazine, etc.). Examples of antimetabolites include, but are not limited to, folic acid analogs (eg, methotrexate) or pyrimidine analogs (eg, fluorouracil, floxouridine, cytarabine), purine analogs (eg, mercaptopurine, thioguanine, pentostatin).

Examples of anti-cancer agents that act by arresting cell growth in the G2-M phase due to microtubule stabilization and that can be used in combination with a Btk inhibitor include, but are not limited to, the following marketed drugs and drugs in the pipeline: erbulozol (also known as R-55104), dolastatin 10 (also known as DLS-10 and NSC-376128), mivobulin isethionate (also known as CI-980), vincristine, NSC-639829, discodermolide (also known as NVP-XX- A-296), ABT-751 (Abbott, also known as E-7010), Altoritins (such as Altoritin A and Altoritin C), Spongistatins (such as Spongistatin 1, Spongistatin 2, Spongistatin 3, Spongistatin 4, Spongistatin 5, Spongistatin 6 spongistatin 7, spongistatin 8 and spongistatin 9), cemadotin hydrochloride (also known as U-103793 and NSC-D-669356), epothilones (such as epothilone A, epothilone B, epothilone C (also known as deoxyepothilone A or dEpoA), epothilone D (also known as KOS-862, dEpoB, and deoxyepothilone B), epothilone E, epothilone F, epothilone B N-oxide, epothilone A N-oxide, 16-aza-epothilone B, 21aminoepothilone B (also known as BMS-310705 ), 21-hydroxyepothilone D (also known as deoxyepothilone F and dEpoF), 26-fluoroepothilone), auristatin PE (also known as NSC-654663), soblidotin (also known as TZT-1027), LS-4559-P (Pharmacia, also known as LS-4577), LS-4578 (Pharmacia, also known as LS-477-P), LS-4477 (Pharmacia), LS-4559 (Pharmacia), RPR-112378

- 44 040198 (Aventis), vincristine sulfate, DZ-3358 (Daiichi), FR-182877 (Fujisawa, also known as WS9885B), GS-164 (Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academy of Sciences), BSF-223651 (BASF, also known as ILX-651 and LU-223651), SAH-49960 (Lilly/Novartis), SDZ-268970 (Lilly/Novartis), AM97 (Armad/Kyowa Hakko), AM-132 (Armad), AM-138 (Armad/Kyowa Hakko), IDN-5005 (Indena), Cryptophycin 52 (also known as LY-355703), AC-7739 (Ajinomoto, also known as AVE-8063 A and CS-39. HCI), AC-7700 (Ajinomoto, also known as AVE-8062, AVE-8062A, CS-39-L-Ser.HCI, and RPR258062A), Vitilevuamide, Tubulisin A, Canadiensole, Centaureydin (also known as NSC-106969) , T138067 (Tularik, also known as T-67, TL-138067 and TI-138067), COBRA-1 (Parker Hughes Institute, also known as DDE-261 and WHI-261), H10 (Kansas State University), H16 ( Kansas State University), oncocidin A1 (also known as WTO-956 and DIME), DDE-313 (Parker Hughes Institute), figianolide B, laulimalide , SPA-2 (Parker Hughes Institute), SPA-1 (Parker Hughes Institute, also known as SPIKET-P), 3-IAABU (Cytoskeleton/Mt. Sinai School of Medicine, also known as MF-569), Narcosine (also known as NSC-5366), Nascapine, D-24851 (Asta Medica), A-105972 (Abbott), Hemiasterlin, 3BAABU (Cytoskeleton/Mt. Sinai School of Medicine, also known as MF-191), TMPN (Arizona State University), vanadocene acetylacetonate, T-138026 (Tularik), monsatrol, inanocin (also known as NSC-698666), 3-1AABE (Cytoskeleton/Mt. Sinai School of Medicine), A-204197 (Abbott), T-607 (Tuiarik, also known as -900607), RPR-115781 (Aventis), eleutherobins (such as desmethyleleuterobine, desethyleleuterobine, isoeleutherobin A and Z-eleutherobin), caribeoside, caribeolin , halichondrin B, D64131 (Asta Medica), D-68144 (Asta Medica), diazonamide A, A-293620 (Abbott), NPI-2350 (Nereus), tacalonolide A, TUB-245 (Aventis), A-259754 (Abbott ), diosostatin, (-)-phenylhistine (also known as NSCL-96F037), D-68838 (Asta Medica), D-68836 (Asta Medica), myoseverin B, D-43411 (Zentaris, also known as D-81862) , A-289099 (Abbott), A -318315 (Abbott), HTI-286 (also known as SPA-110, trifluoroacetate salt) (Wyeth), D-82317 (Zentaris), D-82318 (Zentaris), SC-12983 (NCI), resverastatin phosphate sodium salt, BPR-OY-007 (National Health Research Institutes) and SSR-250411 (Sanofi).

When a subject is suffering from or at risk of developing an autoimmune disease, an inflammatory disease, or an allergy, a reversible or irreversible Btk inhibitor may be used along with one or more of the following therapeutic agents in any combination: immunosuppressants (e.g., tacrolimus, cyclosporine, rapamycin, cyclophosphamide, azathioprine, mercaptopurine, mycophenolate, or FTY720), glucocorticoids (eg, prednisone, cortisone acetate, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, beclomethasone, fludrocortisone acetate, deoxycorticosterone acetate, acids, 2-arylpropionic acid, N-arylanthranilic acids, oxicams, coxibs, or sulfonanilides), specific Cox-2 inhibitors (eg, valdecoxib, celecoxib, or rofecoxib), leflunomide, gold thioglu goat, gold thiomalate, aurofin, sulfasalazine, hydroxychloroquinone, minocycline, TNF-α binding proteins (eg, infliximab, etanercept, or adalimumab), abatacept, anakinra, interferon-β, interferon-γ, interleukin-2, allergy vaccines, antihistamines agents, antileukotrienes, β-agonists, theophylline or anticholinergic agents.

Kits/products.

The present invention also provides kits and articles for use in therapy. Such kits may include a carrier, package, or container that has compartments for multiple containers such as vials, test tubes, and the like, with each container(s) containing(s) one of the elements used in carrying out the method. described in this application. Suitable containers include, for example, vials, bottles, syringes, and assay tubes. Containers can be made from different materials such as glass or plastic.

The products provided by this invention contain packaging materials. Packaging materials for packaging pharmaceutical products are well known to those skilled in the art, see, for example, US Pat. No. 5,323,907. Examples of such packaging include, but are not limited to, blister packs, bottles, and any other means for a particular formulation and route of administration and treatment.

In some embodiments, the pharmaceutical compositions may be in a package or dispenser that may contain one or more unit dosage forms containing a compound of the invention. The package can be made, for example, from metal or polymer foil, for example, in the form of a blister. The packaging or distribution may be accompanied by instructions for use. The package or dispenser may be accompanied by a notice in the form prescribed by the governmental authority regulating the manufacture, use or sale of pharmaceuticals, such notice reflecting that authority's approval of the human or veterinary use of the drug. Such notice may contain the approval of the U.S. Food and Drug Administration (US Food and Drug Administration) the use of a drug or product. There may also be

- 45 040198 prepared compositions containing the compound provided by this invention, in combination with a compatible pharmaceutical carrier, located in a suitable container, along with a label on the use of this compound for the treatment of a particular condition.

For example, the container(s) may(may) include a compound of formula 1 described in this application, optionally in a composition or in combination with another agent described in this application. Such kits may contain a compound and instructions or a label relating to its use in the implementation of the methods described in this application.

The kit typically includes labels listing the contents and/or instructions for use, and may also include a set of instructions.

According to one embodiment of the invention, the label may be on the container or connected to the container. According to one embodiment of the invention, the label may be on the container when the letters, numbers, or other indicia forming the label are molded during the manufacture of the container or engraved on the container itself; the label can be associated with the container when it is inside a reservoir or compartment with a carrier that is also contained in the container, for example in the form of a package insert. The label indicates that the content is being used for a specific therapeutic purpose. Such a label may also show aspects of the use of the contents, including in the implementation of the methods of the invention.

In some embodiments, the pharmaceutical compositions may be in a package or dispenser that may contain one or more unit dosage forms containing a compound of the invention. The package can be made, for example, from metal or polymer foil, for example, in the form of a blister. The packaging or distribution may be accompanied by instructions for use. The package or dispenser may be accompanied by a notice in the form prescribed by the governmental authority regulating the manufacture, use or sale of pharmaceuticals, such notice reflecting that authority's approval of the human or veterinary use of the drug. Such notice may contain the approval of the U.S. Food and Drug Administration (US Food and Drug Administration) the use of a drug or product. Compositions may also be prepared containing a compound of this invention in combination with a compatible pharmaceutical carrier, provided in a suitable container, along with a label stating that the compound is used to treat a particular condition.

Examples

The following ingredients, formulations, methods and procedures for carrying out this invention are as described above.

Example 1 Preparation of crystalline forms of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1Hpyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop- 2-en-1-one (compound 1).

Form A - method 1.

An amorphous compound of formula 1 (about 15 mg) was placed in a vessel. Ten volumes (150 μl) of the solvent [methyl tertiary butyl ether (MTBE), diisopropyl ether (DIPE), ethyl acetate, isopropyl acetate, isopropyl alcohol, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), acetone, methanol, nitromethane, 10 % aqueous acetone or 10% aqueous isopropyl alcohol]. The vessel was sealed and placed in a shaker at 50°C for 1 h.

If a suspension formed, another thirty volumes of solvent were added (total 600 µl), then the suspension was again heated at 50°C for another 1 hour. temperature of 50°C for 1 h and then cooled to 0°C at a rate of 0.1°C/min, then kept at 0°C overnight. If a suspension was obtained, the solids were filtered off under vacuum to obtain form A of compound 1; the solution was heated to room temperature for slow evaporation through a small diameter hole to obtain form A of compound 1.

Form A - method 2.

Amorphous compound 1 (20 mg) was placed in a vessel, the solvent was added [heptane (10 vols), dioxane (1 vol), toluene (10 vols), MTBE (10 vols), DIPE (10 vols), anisole (1 vol), ethyl acetate (10 vols), isopropyl acetate (10 vols), tetrahydrofuran (1 vol), DCM (1 vol), MIBK (10 vols), MEK (10 vols), acetone (10 vols), methanol (10 vols), ethanol ( 10 vols), acetonitrile (10 vols), nitromethane (1 vol), water (10 vols) or 10% aqueous isopropyl alcohol (1 vol)].

The sealed vessel was placed in a maturation chamber (cycles between 50°C and room temperature for 4 hours each) for 5 days, then the solids were filtered under vacuum to obtain Form A of compound 1.

In some embodiments, amorphous Compound 1 is prepared by dissolving Form A of Compound 1 (about 500 mg in 10 ml dichloromethane (DCM)). The solvent was removed in a rotary evaporator fairly quickly to prevent crystallization to give amorphous compound 1.

- 46 040198

Form A - method 3.

In a clean round bottom flask, 12 g of compound 1 was dissolved in 120 ml of methanol by heating to a temperature of 45°C while stirring with a magnetic stirrer.

72 ml of water was added to a warm solution of dissolved compound 1 over 45 min, maintaining the temperature inside the vessel at 45°C. The solution slowly turned into a suspension, it was stirred for 3 h at elevated temperature. A sample of the suspension was taken, filtered and dried. The suspension was allowed to cool to room temperature and stirred for at least 16 hours.

Another sample of the suspension was taken, filtered and dried. The solids were filtered off, washed with 50 ml of 3:2 methanol:water, and dried on the filter for 40 h.

Form A yield was 9.6 g (melting point: first sample ~152°C, second sample ~154°C, main batch ~154°C).

Form A was also prepared in a similar manner using aqueous acetone, ethanol and n-propanol.

Form B - method 1.

Compound 1 Form A was placed in a vessel and dissolved in methanol (2 ml). The solution was heated to a temperature of 50°C to ensure complete dissolution, then cooled to 5°C. At a temperature of 5°C, water (200 μl) was added to the solution at the moment when the sample became cloudy (total 1000 μl). Form C embryos of Compound 1 were added immediately after the appearance of turbidity. The suspension was stirred at 5°C for one day. An aliquot was taken with a pipette for analysis by powder X-ray diffraction analysis (XRPD), maintaining the mass of the sample under the same conditions. XRPD showed low crystallinity of the obtained material, so the sample was kept at 5°C for another 3 days. Thereafter, reanalysis of an aliquot of the sample showed that the material had converted to form B of compound 1. The sample was isolated by vacuum filtration to obtain form B of compound 1.

Form B - method 2.

Form A of compound 1 (about 500 mg) was placed in a vessel and dissolved in methanol (4 ml) at a temperature of 5°C. The solution was cooled to 25° C., leaving the solution in the vessel. Water (500 µl, 2 ml total) was added until a cloudy solution was obtained. The resulting suspension was stirred for 10 minutes. To assess the material, an aliquot of the suspension was taken with a pipette for powder X-ray diffraction analysis, at which time the sample was stirred at 25°C for 1 h; however, the material had very low crystallinity. After stirring for 1 hour at 25°C, the sample was kept at 5°C for 3 days. Another aliquot was then pipetted for XRPD. The remainder of the suspension was vacuum filtered and dried at 25°C under vacuum overnight to give form B of compound 1.

Form C.

In a clean round bottom flask, 2.0 g of compound 1 was suspended in 25 ml of methanol and heated to a temperature of 50°C. A warm solution of dissolved compound 1 was filtered into a clean round bottom flask. The purified solution was allowed to cool to room temperature while stirring with a magnetic stirrer. The solution was stirred for 14 h, it slowly turned into a suspension. The solids were filtered off, washed with 5 ml of methanol and dried on the filter for 20 h, then at 50°C in an oven under vacuum for 8 h. The yield of form C of compound 1 was 1.4 g (melting point = ~132°C) .

Form D.

A dry mixture (about 5 mg of each component) was prepared using two forms selected from form A, form B or form C of compound 1. The suspension obtained from amorphous compound 1 in MIBK was filtered to obtain a saturated solution. To prepare a new suspension, ten volumes (100 μl) of this saturated solution were added to the dry mixture. The suspension was stored at 5°C for 3 days, then filtered under vacuum to obtain form D of compound 1.

Form E.

Amorphous compound 1 was placed in a vessel, then the embryos of form C of compound 1 (about 5 mg) were added. Ten volumes of toluene (200 μl) were added to the vessel to obtain the suspension. The vessel was sealed and left to mature (cycles changed from 50° C. to room temperature, 4 h each) for one day. One aliquot was pipetted for XRPD, TGA and DSC. These analyzes indicated the preparation of form E of compound 1. However, it was found that this compound, after standing at room temperature overnight and drying at a temperature of 40°C under vacuum for one day, was converted to form A of compound 1.

Form F.

In a clean 20 ml scintillation vessel, 200 mg of compound 1 and 50 mg of activated charcoal were suspended in 4 ml of methanol and heated to a temperature of 50°C. The resulting mixture was stirred at 50°C for 2.5 hours. The warm solution of compound 1, after removing the carbon, was filtered through a syringe filter into another clean vessel with a volume of 20 ml. The solution was allowed to cool to room temperature. The solution was then left to stand without stirring for a week until some crystals began to form. Over a period of more than 6 weeks. the bottom of the vessel was covered with large crystals. These crystals were kept under supersaturated methanol solution in preparation for analysis.

Example 2 Powder X-Ray Diffraction (XRPD)

Powder X-ray patterns were obtained on a Bruker AXS C2 GADDS or Bruker AXS D8 diffractometer.

Bruker AXS C2 GADDS.

Powder X-ray diffraction patterns were obtained on a Bruker AXS C2 GADDS diffractometer using CuKa radiation (in 40 kV, 40 mA mode), an automated XYZ stage, a laser video microscope for positioning autosamples, and a HiStar 2D surface detector. The X-ray optics consisted of a single Gobel multilayer mirror coupled to a collimator with a pinhole of 0.3 mm. Weekly data collection was carried out using NIST 1976 certified Corundum (flat plate). The beam divergence, namely the effective size of the diffracted X-ray beam on the sample, was about 4 mm. A θ-θ continuous sweep type was used with a sample-detector distance of 20 cm, resulting in a 2θ interval of 3.2-29.7°. Usually, the exposure time of the sample under the action of X-rays was 120 s. The computer program GADDS for WNT 4.1.16 was used for data collection, and the data was analyzed and presented using the Diffrac Plus EVA v11.0.0.2 or v13.0.0.2 software package.

Environmental conditions.

At ambient conditions, powder samples were used without grinding in the form of flat plates. Approximately 1-2 mg of the sample was lightly pressed against the glass slide to obtain a flat surface.

A mode that does not match the environmental conditions.

Samples under conditions not corresponding to environmental conditions were mounted on a silicon wafer with a thermally conductive connection. The sample was then heated to the appropriate temperature at a rate of 10° C./min (unless otherwise noted) and then held under isothermal conditions until data collection began.

Diffractometer Bruker AXS D8 Advance.

Powder X-ray diffraction patterns were taken on a Bruker D8 diffractometer using CuKa radiation (at 40 kV, 40 mA), a θ-2θ goniometer and V4 divergence and receiving slits, a Ge monochromator, and a Lynxeye detector. Data were taken using the certified corundum standard (NIST 1976). The Diffrac Plus XRD Commander v2.5.0 computer program was used and data was analyzed and presented using the Diffrac Plus EVA v11.0.0.2 or v13.0.0.2 software package. Used powder samples without milling in the form of flat plates in ambient conditions.

The sample was carefully placed into the cavity cut in the cleaned silicone wafer (510). During the analysis, the sample was rotated in its plane.

Used parameters:

angular range: 2 to 42° 2θ, step size: 0.05° 2θ, acquisition time: 0.5 s/stage. XRPD form A.

The X-ray powder diffraction pattern of Form A is shown in FIG. 1. Characteristic peaks were observed at 2-θ angles of 5.7±0.1°, 13.6±0.1°, 16.1±0.1°, 18.9±0.1°, 21.3±0.1°, and 21.6±0.1°.

The crystallinity did not change after one week storage at 40°C and 75% relative humidity (RH) or after one week storage at 25°C/97% RH.

XRPD form B.

The X-ray powder diffraction pattern of Form B is shown in FIG. 5. Characteristic peaks were observed at 2-θ angles of 5.2±0.1°, 10.2±0.1°, 16.5±0.1°, 18.5±0.1°, and 20.8±0.1°.

The crystallinity did not change after one week storage at 40°C and 75% relative humidity (RH) or after one week storage at 25°C/97% RH.

XRPD form C.

An X-ray powder diffraction pattern of Form C is shown in FIG. 9. Characteristic peaks were observed at 2-θ angles of 7.0±0.1°, 14.0±0.1°, 15.7±0.1°, 18.2±0.1°, 19.1±0.1°, 19.5±0.1°, 20.3±0.1°, 22.1± 0.1° and 22.9±0.1°.

The crystallinity did not change after one week storage at 40°C and 75% relative humidity (RH) or after one week storage at 25°C/97% RH.

XRPD form D.

The X-ray powder diffraction pattern D is shown in FIG. 12. Characteristic peaks were observed at 2-θ angles of 7.2±0.1°, 8.0±0.1°, 9.2±0.1°, 14.5±0.1°, 18.5±0.1°, 19.5±0.1°, 20.7±0.1°, 21.0± 0.1°, 21.9±0.1° and 22.4±0.1°.

- 48 040198

XRPD form E.

The X-ray powder diffraction pattern of Form E is shown in FIG. 14. Characteristic peaks were observed at 2-θ angles of 7.8+0.1°, 8.8+0.1°, 16.1+0.1°, 18.1+0.1°, 19.3+0.1°, 19.5+0.1°,

20.5+0.1°, 21.6+0.1° and 25.2+0.1°.

XRPD form F.

A simulated XRPD pattern was generated for Form F. This XRPD pattern was generated from the single crystal data obtained in Example 3 (cif file) using the Mercury CSD v3.1 program (C.F. Macrae et al., J. Appl. Cryst. (2006), 39-3, 453-457) (XRPD pattern parameters: CuKa 1.54056; start/end 2/43 2θ°; PWHW (2θ°) 0.1). The data was then saved as a Raw file. To obtain 2θ°/intensity (%) peaks, the Raw file was processed using the Diffrac Plus EVA v. 15.0.0.0.

The simulated X-ray powder diffraction pattern F is shown in FIG. 16. Characteristic peaks were observed at 2-θ angles of 6.2+0.1°, 10.1+0.1°, 17.6+0.1°, 18.6+0.1°, 20.0+0.1°, 20.4+0.1°, 20.7+0.1°, 22.4+ 0.1°, 23.0+0.1°, 23.2+0.1°, 24.4+0.1°, 25.1+0.1°, 27.6+0.1°, 29.3+0.1° and 29.7+0.1°.

Example 3 X-ray diffraction pattern of a single crystal.

Data for a single crystal was obtained and processed as follows:

Diffractometer: SuperNova, Dual, C at 0, Atlas

Light source: SuperNova (Cu) X-ray Source, CuKa

Data Acquisition Method: Omega Axis Scan

Acquisition Theta Angle Range: 9.11 to 74.49°

Index range: -11< h< 12, -12 < k< 12, -18 < /< 18 Reflections: 22842 Independent Reflections 9278 [R(int) = 0.0407] Field of independent reflections: 99.4%

Variation of test reflections: n/a

Absorption Correction: semi-empirical based on equivalents Max. and min. transmission 1.00000 and 0.73583 Methodology for solving the structure: direct method Solution solution program: SHELXS-97 (Sheldrick, 1990)

Least squares technique in full-matrix approximation in F^·

Refinement program: SHELXL-97 (Sheldrick, 1997) Minimized function: ^w(F ₀ ² -F _c y Data/Restrictions/Parameters: 9278/3/660 Compliance criterion by 1.004 Anglach 0.000

End indices R:

9185 data; Ι>2σ(Ι) RI = 0.0414, wR2 = 0.1144 All data: RI = 0.0417, wR2 = 0.1149 Weighing scheme: calculated w=l / [σ ² (Fo ² )+(0.0810P) ² +0.2800P] where P=(F0 ² +2F _c ² )/3

Absolute Structure Parameter: -0.01(13)

Extinction coefficient: 0.0013(3)

The most pronounced peak and hole: 0.320 and -0.285 eA ^-3

Form F was characterized by unit cell parameters approximately equal to the following parameters at a temperature of about 100(2) K:

- 49 040198

Formula C53H60N12O7 Molecular weight 977.13 Crystal system Triclinic Symmetry group P1 A 9.6332(3) A □ 105.762(3)° Kommersant 9.7536(4) A □ 95.132(2)° With 15.0592(4) A □ 111.332(3)° V 1240.15(7) A ³ Z 1 Density (calc.) 1.308 mg/ ^m3 Adsorption coefficient 0.726 mm1 Wavelength 1.54178 A F(000) 518 T 100(2) K

Example 4 Fourier Transform - PC Spectra (FTIR).

Data were acquired on a Perkin-Elmer Spectrum spectrometer equipped with an Attenuated Total Reflectance (ATR) sample collector. Data were collected and analyzed using Spectrum v5.0.1 software.

The PC spectra for Form A are shown in FIG. 2. Characteristic bands were observed with a frequency of 1584 cm' ¹ , 1240 cm' ¹ , 1147 cm' ¹ , 1134 cm' ¹ , 1099 cm' ¹ , 1067 cm' ¹ , 985 cm' ¹ and 953 cm' ¹ .

The PC spectra of Form B are shown in FIG. 6. Characteristic bands were observed with a frequency of: 1586 cm' ¹ , 1573 cm' ¹ , 1562 cm' ¹ , 1229 cm' ¹ , 1166 cm' ¹ , 1141 cm' ¹ , 1103 cm' ¹ , 1056 cm' ¹ , 1033 cm ' ¹ and 982 cm' ¹ .

Example 5 Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA)

DSC data were obtained on a TA Instruments Q2000 equipped with an automatic sampler (for 50 samples). Heat capacity calibration was performed using sapphire, energy and temperature calibration was performed using indium. Typically, 0.5-3 mg of each sample was placed in an aluminum crucible with a hole and heated at a rate of 10°C/min from 25 to 300°C. A stream of dry nitrogen was passed over the sample at a rate of 50 ml/min, unless otherwise indicated. The temperature at DSC was increased at a rate of 2°C/min, using temperature change parameters of ±0.318°C (amplitude) every 60 s (period). The Advantage software for Q Series v2.8.0.392 and Thermal Advantage v4.8.3 were used, and the data was analyzed using the Universal Analysis v4.4A software package.

TGA data were obtained on a TA Instruments Q500 TGA equipped with a 16-sample auto-sampler. The temperature was calibrated using certified material Alumel and nickel. Typically, 310 mg of each sample was placed in a pre-weighed aluminum DSC tray and heated at a rate of 10°C/min from room temperature to 350°C. Dry nitrogen was passed over the sample at a rate of 60 ml/min unless otherwise noted. The Advantage software for Q Series v2.8.0.392 and Thermal Advantage v4.8.3 were used as controls; the data were analyzed using the Universal Analysis v4.4A software package.

Form A.

The DSC and TGA thermograms for Form A are shown in FIG. 3 and 4, respectively. No weight loss was observed. The material was anhydrous.

On the DSC curve (heating rate was 10°C/min or 20°C/min), an endothermic effect was observed starting at about 154° with a peak (maximum) at about 157°C. An exothermic effect was observed at 159°C.

Form B.

The DSC and TGA thermograms for Form B are shown in FIG. 7 and 8, respectively. No weight loss was observed. The material was anhydrous.

On the DSC curve (heating rate was 10°C/min or 20°C/min), an endothermic effect was observed starting at about 99-106°C with a peak (maximum) at about 115-118°C.

Form C.

The DSC and TGA thermograms for Form B are shown in FIG. 7 and 8, respectively. No weight loss was observed. The material was anhydrous.

On the DSC curve (heating rate was 10°C/min or 20°C/min), an endothermic effect was observed starting at about 134-135°C with a peak (maximum) at about 137-139°C.

Form D.

The TGA thermogram for Form D is shown in FIG. 13.

The total weight loss was 16.6-17.8%, which is equivalent to about 1 mol of MIBK, or at the stage

-50040198

1 or at stage 2.

Form E.

The DSC and TGA thermograms for Form E are shown in FIG. 15.

In thermogravimetric analysis, a weight loss of 16.5% w/w was observed associated with 2 endothermic effects in DSC at 85° C. (onset) and 151° C. (onset), which may correspond to a desolvation phenomenon.

Example 6 Vapor Sorption in Thermogravimetric Analysis (GVS).

Sorption isotherms were obtained using the SMS DVS Intrinsic moisture sorption analyzer, the operation of which was controlled using the DVS Intrinsic Control v1.0.0.30 computer program. The sample temperature was maintained at 25°C using control units. Humidity was controlled by mixing flows of dry and wet nitrogen supplied at a total rate of 200 ml/min. Relative humidity was measured with a calibrated Rotronic moisture meter (dynamic range 1.0–100% RH) located near the sample. The weight change (mass relaxation) of the sample as a function of % RH was constantly monitored using a microbalance (accuracy ±0.005 mg). Typically, a sample weighing 5-20 mg was placed in a weighed wire basket under ambient conditions. The sample was placed and removed at 40% RH and at a temperature of 25°C (typical environmental conditions). The moisture sorption isotherm was obtained as described below (2 measurements representing one complete cycle). The standard isotherm was obtained at a temperature of 25°C at intervals equal to 10% RH within 090% RH. The analysis data were processed using Microsoft Excel using the DVS Analysis Suite v6.0.0.7 program. The sample was removed after obtaining the isotherm and analyzed by XRPD.

Table 1

SMS DVS detection method parameters

Options Quantities Adsorption - cycle 1 40-90 Desorption / adsorption - cycle 2 90 - 0, 0 - 40 Intervals (%RH) 10 Number of cycles 2 Flow rate (ml/min) 200 Temperature (°C) 25 Stability (°C/min) 0.2 Sorption time (hours) 6 hour break

Form A.

The weight change was less than 0.3% w/w. in the range of 0-90% RH. The material was not hygroscopic. After determining GVS, no noticeable changes were observed.

Form B.

The weight change was 2.3% w/w. in the range of 0-90% RH. Hysteresis was not observed. After determining the GVS (gravimetric vapor sorption), there were no noticeable changes in the diffraction pattern.

Example 7 Thermodynamic solubility in water.

Water solubility was determined by suspending sufficient compound in water to give a final maximum free form concentration of the parent compound of >10 mg/mL. The suspension was allowed to stand at 25° C. for 24 hours and then the pH value was measured. The suspension was then filtered through a glass fiber filter C. The filtrate was then diluted until an appropriate dilution factor, for example 101, was obtained.

Solubility was quantified by HPLC using a standard reference solution containing a solution of the compound in dimethyl sulfoxide at a concentration of approximately 25 mg/mL. Various volumes of standard solution, dilute solution, and undiluted solution were injected into the column. Solubility was determined from the area of the peaks, determined by integrating the peak at the same retention time as for the main peak using the standard solution.

- 51 040198

table 2

Parameters for determination of solubility by HPLC method

Method type: Reverse phase with gradient elution Column: Phenomenex Luna, Cl8 (2) 5 µm, 50 x 4.6 mm Column temperature (°C): 25 Standard injections (µl) 1,2,3, 5, 7, 10 Trial injections (µl) 1, 2, 3, 10, 20, 50 Detection: wavelength, wavelength (nm) 260, 80 Flow rate (ml/min): 2 Phase A: 0.1% TFA in water Phase B: 0.085% TFA to acetonite] zile Program: Time (min) % phase A % phase B 0.0 95 5 1.0 80 20 2.3 5 95 3.3 5 95 3.5 95 5 4.4 95 5

The analyzes were performed on an Agilent HP 1100 system equipped with a diode array detector using the ChemStation software vB.02.01-SR1 computer program.

The solubility of form A in aqueous solution at various pH values is shown in table. 3.

Table 3

Solubility of form A in aqueous solution at various pH values

pH value Received concentration (mg/ml) 1.2 1.3 1.64 1.07 1.95 0.82 3 0.10 4 0.022 5 0.017 6 0.015 8 0.013 9 0.020 10 0.010

The thermodynamic solubility in water of Form B at pH 7.42 was 0.0096 mg/mL.

Example 8. Determination of the degree of chemical purity.

HPLC was performed on an Agilent HP1100/1200 system equipped with a diode array detector using the Chemstation computer program, following the method detailed below.

Table 4

Method parameters

Method type: Reverse phase with gradient elution Test sample: ~ 0.1 mg/ml at 60:40 v/v H ₂ O:ACN Column: Gemini-NX C18, 4.6 x 150 mm, 3 µm Column temperature (°C): 40 Injection volume (µlP □ 100 Detection: Wavelength, bandwidth (nm) 260, 210 to 500 nm Flow rate (ml/min): 1.5

- 52 040198

Phase A: 0.1% TFA in water Phase B: 0.1% TFA in acetonitrile Program: Time (min) % phase A % phase B 0 75 25 10 70 thirty thirty 65 35 45 35 65 46 10 90 50 10 90 51 75 25 60 75 25 Retention time : ~ 20 min Washing the needle: methanol : water (8:2)

In some embodiments, HPLC indicated that Form A was more than 96% pure. In some embodiments, HPLC data showed that Form A was more than 97% pure. In some embodiments, the purity of Form A was determined by HPLC to be greater than 98%. In some embodiments, HPLC indicated that Form A was more than 99% pure. In some embodiments, HPLC showed that Form A was 99.8% pure.

In some embodiments, HPLC showed that Form C was more than 95% pure. In some embodiments, HPLC indicated that Form C was more than 96% pure. In some embodiments, HPLC showed that Form C was more than 97% pure. In some embodiments, HPLC showed that Form C was more than 98% pure. In some embodiments, Form C is more than 99% pure. In some embodiments, HPLC indicated that Form C was 99.4% pure.

Example 9 Determination of the degree of chiral purity.

The chiral purity of compound 1 was determined by normal phase HPLC using a Lux Cellulose-1 chiral column.

The mobile phase consisted of 20% isopropyl alcohol and 80% hexane.

Presence of enantiomers it was determined at a wavelength of 260 nm. According to one embodiment of the invention, Compound 1 was dissolved in 7:3 hexane:isopropyl alcohol (IPA) to a concentration of approximately 0.2 mg/mL and the chiral purity of the compounds was determined.

The content of the R-enantiomer was determined by normalizing the area of the peaks of the enantiomers and expressed as a weight ratio. In some embodiments, a sample of Compound 1 contained less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% of the (S) isomer.

Solid oral dosage forms.

In some embodiments, crystalline 1-(3-(4-amino-3-(4-phenoxyphenyl)-1Hpyrazolo[3,4-b]pyrimidin-1-yl)piperidin-1-yl)prop-2-en- 1-it is part of a solid oral dosage form. In some embodiments, 1-(3-(4-amino-3-(4-phenoxyphenyl)-1Hpyrazolo[3,4-b]pyrimidin-1-yl)piperidin-1-yl)-prop-2-en-1- it is included in the tablets. In some embodiments, crystalline 1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4d]pyrimidin-1-yl)piperidin-1-yl)-pron-2-en-1 - it is a part of pills (pellets). In some embodiments, crystalline 1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-ene -1-it is part of the capsules. In some embodiments, crystalline 1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-ene1 -on is placed in capsules without excipients or together with excipients. In any of these variants, crystalline 1 - (3 - (4-amino-3 - (4-phenoxyphenyl) -1 H-pyrazolo[3,4-d] pyrimidin-1 -yl) piperidin-1 yl) prop-2- en-1-one may be Form A. In any of these embodiments, crystalline 1(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl )piperidin-1-yl)prop-2-en-1-one may be Form B. In any of these embodiments, crystalline 1-(3-(4-amino-3-(4phenoxyphenyl)-1H-pyrazolo [3 ,4-d] pyrimidin-1-yl)piperidin-1-yl)-prop-2-en-1-one may be Form C. In any of these embodiments, crystalline 1-(3-(4-amino-3 -(4-phenoxyphenyl)-Spyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one may be Form D. In any of these embodiments, the crystalline 1- (3-(4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one may be Form E In any of these variants, crystalline )prop-2-en-1-one may be Form F. In any of these embodiments, crystalline 1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d ]pyrimidin-1-yl)piperidin-1 yl)prop-2-en-1-one may be a mixture of two crystalline forms selected from the group consisting of Form A, Form B, Form C, Form D, Form E, and form F.

- 53 040198

Example 10 Capsule Formulations

According to one embodiment, capsules containing Compound 1 for administration to humans are prepared from the following components.

Table 5

The composition of the capsules

Component Capsule 40 mg Capsule 140mg Capsule 140mg Capsule 200mg weight/weight % mg/cap. weight/weight % mg/cap. weight/weight % mg/capsulu weight / weight % mg/caps. Crystallin, compound 1 29.6 40.0 60.9 140.0 42.4 140.0 74.1 200.0 Microcrystal, cellulose NF 57.4 77.5 23.0 53.0 45.9 151.4 8.5 23.0 Croscarmellose sodium NF 10.0 13.5 10.0 23.0 7.0 23.0 10.0 27.0 Sodium lauryl sulfate NF 3.0 4.0 6.1 14.0 4.2 14.0 7.4 20.0 Magnesium Stearate NF No tribute. No tribute. No tribute. No tribute. 0.5 1.6 NA NA

In some embodiments, the method for making capsules includes the following steps: weighing a specified number of components, mixing these components, adding the mixture to an appropriately sized capsule, and closing the capsule. In some embodiments, the capsules are stored at room temperature for an extended period of time prior to use.

Example 11 Immediate release tablets.

According to some options, tablets are made from the components listed in table. 6.

Table 6

Components of the composition of tablets

Ingredient Quantity Crystallin, compound 1 from 5% to 50% Hypromellose from 2% to 10% Croscarmellose sodium from 0% to 15% Microcrystal, cellulose from 5% to 50% Lactose from 10% to 75% magnesium stearate from 0.25% to 2.5% Total Tablet weight: 300 mg to 1000 mg

Tablets are usually obtained by granulation (dry, wet or melt) or direct compression.

Example 12 Study of the safety and tolerability of compound 1 in chronic lymphocytic leukemia.

Purpose: The purpose of this study is to establish the safety and optimal dose of oral compound 1 (420 mg/day) in patients with B-cell chronic lymphocytic leukemia (CLL)/small cell lymphocytic lymphoma (SLL)/diffuse well-differentiated lymphocytic lymphoma.

Primary efficacy criteria: safety and tolerability of compound 1 (frequency, severity and similarity of adverse effects).

Secondary efficacy criteria: determination of pharmacokinetics and pharmacodynamics. Tumor response - overall response determined according to the latest guidelines for CLL and SLL (B-cell lymphoma) and duration of response.

Eligibility: Patients 18 years of age or older may be of either gender.

Inclusion Criteria:

1. Non-drug treated patients only: Men and women 65 years of age or older with a confirmed diagnosis of CLL/SLL who require treatment in accordance with NCI (National Cancer Institute) or International Task Force guidelines 11-14.

2. Relapsed/poorly responding group only: men and women aged 18 years and older with confirmed diagnosis of relapsed or poorly responding CLL/SLL (refractory patients) who are not responding to treatment (namely, those who have received 2 or more course

- 54 040198 treatment of CLL/SLL with a negative result, or patients with CLL who, at least during one course of treatment, should have taken a purine analog (eg, fludarabine).

3. Patient weight was >40 kg.

4. ECOG (Eastern Associated Oncology Group) General Condition Score <2.

5. Consent to use contraceptives during the study and for 30 days after receiving the last dose of the study drug if the patients were sexually active and capable of bearing children.

6. Willingness and ability to participate in all required examinations and protocol procedures, including swallowing capsules without difficulty.

7. The ability to understand the purpose and risk of the research, and to give dated and informed consent and permission to use legally protected health information (in accordance with national and local privacy regulations).

Exclusion Criteria:

1. Presence of a life-threatening disease, medical condition, or organ system dysfunction that, in the opinion of the Investigator, could impair subject safety, interfere with absorption or metabolism of orally administered Compound 1, or result in unnecessary risk of confounding study results.

2. Any type of immunotherapy, chemotherapy, radiotherapy or experimental therapy within 4 weeks. before the first dose of the test drug (the use of corticosteroids for the treatment of symptoms of the disease was allowed, but in this case, the drug was washed out for one week before the administration of the test drug).

3. Damage to the central nervous system (CNS) in the presence of lymphoma.

4. Radical surgery within 4 weeks prior to administration of the first dose of the test drug.

5. Creatinine content >1.5 x hospital upper limit (ULN); total bilirubin x hospital upper limit (ULN) (unless due to Gilbert's disease) and aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5 x ULN, unless due to disease.

6. Concomitant use of drugs known to cause long interval syndrome or torsades de pointes.

7. Significant cardiogram (ECG) abnormalities, including left atrioventricular bundle branch block, second-degree type II atrioventricular block, third-degree heart block, bradycardia, and corrected QT interval >470 ms. Breastfeeding or pregnant women.

Example 13 Safety and Efficacy of Compound 1 in Patients with Recurrent/Recalcitrant Mantle Cell Lymphoma.

The primary objective of this study is to evaluate the efficacy of Compound 1 in subjects with recurrent mantle cell lymphoma (MCL)/refractory subjects. Another aim of the study was to evaluate the safety of compound 1 used in this patient population on a fixed daily regimen (560 mg/day in capsule form).

Main performance criteria: determination of the number of test participants responding to the use of compound 1.

Secondary efficacy criteria: determination of the number of participants with adverse (undesirable) effects as a measure of the safety and tolerability of this compound. Determination of pharmacokinetics for diagnosing the body's response to the test drug. Patient outcomes (determining the number of participants who reported results in a health-related quality of life measurement).

Eligibility: Age 18 and over; both sexes are suitable.

Inclusion Criteria:

1. Men and women aged 18 and over. ECOG (Eastern Associated Oncology Group) General Condition Score <2.

2. The presence of pathologically confirmed MCL, with documentation of either overexpression of cyclin D1 or t (11; 14), or documentation confirming that the largest diameter in the imaging of the tumor cross section is >2 cm and measured in two perpendicular directions. No evidence of achieving at least a partial response (PR) in the presence of disease progression or documented disease progression since the most recent course of treatment. Passing at least one, but not more than five, previous courses of MCL treatment. (Note: Patients previously treated with >2 cycles of bortezomib, either as the sole agent or as part of combination therapy, were considered to have been treated with bortezomib.) The desire and ability to accept

- 55 040198 participation in all required examinations and protocol procedures, including swallowing capsules without difficulty. The ability to understand the purpose and risk of the study, and to provide dated and informed consent and permission to use legally protected health information (in accordance with national and local privacy regulations).

Main exclusion criteria: previous chemotherapy within 3 weeks, administration of nitrosoureas within 6 weeks, use of therapeutic anti-cancer antibodies within 4 weeks, administration of radio- or toxin-immunoconjugates within 10 weeks, radiation therapy within 3 weeks, or presence of radical surgery in two weeks prior to the first dose of the test drug. The presence of a life-threatening disease, medical condition, or organ system dysfunction that, in the opinion of the Investigator, could impair subject safety, interfere with absorption or metabolism of Compound 1 oral capsules, or result in unnecessary risk of confounding study results. Serious cardiovascular disease such as uncontrolled arrhythmias, congestive heart failure, or myocardial infarction within six months prior to study entry, or any New York City Functional Classification Class 3 or 4 heart disease. Presence of malabsorption syndrome, disease significantly affecting the gastrointestinal tract, or resections of the bowel or small intestine, or ulcerative colitis, symptomatic bowel inflammation, or partial or complete bowel obstruction. Any of the following laboratory abnormalities: absolute neutrophil count (ANC) <750 cells/mm ³ (0.75 x 109/L) if there is no documented evidence of bone marrow involvement. 2. Platelet count <50,000 cells/mm ³ (50x109/l) regardless of blood transfusion, if there is no documented evidence of bone marrow damage. 3. Serum levels of aspartate transaminase (AST/SGOT) or alanine transaminase (ALT/SGPT) >3.0 x hospital upper limit (ULN). 4. Creatinine >2.0 x ULN.

Example 14 Phase 3 study in patients with high risk chronic lymphocytic leukemia and small lymphocytic lymphoma using a combination of compound 1 and rituximab.

Purpose: The purpose of this clinical study is to investigate whether Compound 1, in combination with rituximab, helps to control the course of chronic lymphocytic leukemia (CLL) and small cell lymphocytic lymphoma (SLL). The safety of this compound has also been studied. Rituximab (375 mg/m ² ) was intravenously administered on days 1, 8, 15 and 22 during the treatment cycle, then continued to be administered once a day only on day 1 during cycles 2-6.

Compound 1 was started orally on Day 2 of Cycle 1 at a dose of 420 mg (3 x 140 mg, capsules) and continued to be administered every day.

Key performance criteria: progression-free survival (PFS). [Study duration: 3 months] - progression-free survival was defined as the time interval from the start of treatment to disease progression or death, whichever came first. All patients with complete remission (CR), partial remission (PR), or stable disease (SD) were included in the progression-free survival group. Survival or time to disease progression was determined using the Kaplan-Meier method.

Secondary efficacy criteria: toxicity [study period: 3 months] -toxicity was determined by type, frequency and severity. The highest toxicity for each patient was tabulated for selected side effects and laboratory evaluation. Toxicity (Grade 3 or 4) monitored by a Bayesian model (β-nominal) assuming a priori the possibility of toxicity after reaching β (1,1).

Compliance with the requirements: the age of patients is 18 years and older, participation of both men and women is possible.

Inclusion Criteria:

1. Patients must have been diagnosed with high-risk CLL/SLL and must have received up to 3 lines of prior therapy. The possibility of high risk in CLL and SLL was determined by the presence of a 17p deletion, or an 11q deletion, or a TP53 mutation. Any patient with CLL and SLL who experienced a short remission period of less than 3 years after previous first-line chemoimmunotherapy, such as an FCR program, was also included in the high-risk group for CLL/SLL, regardless of the presence or absence of cytogenetic abnormalities. .

2. Patients with CLL and SLL with a 17p deletion or a TP53 mutation may not have received any prior therapy provided that treatment of CLL/SLL patients with standard advanced chemoimmunotherapy has been poor, such patients have met inclusion requirements if they have not been treated, or if they received up to 3 lines of prior therapy.

3. Patients must have been eligible for treatment according to the 2008 IWCLL criteria

- 56 040198

Criteria (International Workshop on Chronic Lymphocytic Leukemia).

4. The age of the patient when signing the informed consent must be 18 years and above. Understanding and voluntary signature on the informed consent form. Ability to cope with research and follow-up procedures.

5. The general condition in accordance with the requirements of ECOG/WHO should have been equal to 0-1 points.

6. Patients of reproductive potential must have agreed to the use of highly effective means of preventing pregnancy (eg, condoms, implants, injections, combined oral contraceptives, certain intrauterine devices [IUDs], abstaining from sexual activity, or having a sterilized sexual partner) during the procedure. study or within 30 days after the last dose of the study drug. Women of childbearing potential include any woman who has begun menstruating and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy), or who has reached post-menopausal age. Postmenopause was defined as follows: period without menses >12 consecutive months with no other cause and documented evidence that serum follicle-stimulating hormone (FSH) >35 m.u./ml; a man was considered to be of reproductive potential unless he was sterilized by surgery.

7. Adequate kidney and liver function, as evidenced by all of the following: total bilirubin <1.5x upper limit of hospital normal (ULN), except for patients with elevated bilirubin due to Gilbert's disease, who were allowed to participate in the study; ALT content <2.5 x ULN; and calculated creatinine clearance (CrCl) >30 ml/min, unless associated with disease; the calculation was made according to the Cockcroft-Gault equation.

8. No previous malignancy within 3 years, except for those currently being treated for basal cell carcinoma, squamous cell carcinoma of the skin, or in situ cervical or breast cancer.

9. Urine pregnancy test (within 7 days from the first day), which was required for women of childbearing potential.

Exclusion Criteria: 1. Pregnant or breastfeeding women. 2. Treatment including chemotherapy, chemoimmunotherapy, monoclonal antibody therapy, radiotherapy, high-dose corticosteroid therapy (greater than 60 mg prednisone or its equivalent daily), or immunotherapy within 21 days prior to patient selection or during the study. 3. Receipt of study drug within 30 days prior to administration of the first dose of study drug, or administration of Compound 1 earlier. If the patient had taken the study agent prior to the specified time point, the toxicity associated with the study drug should have returned to Grade 1 or below before the first dose of the study drug was administered. 4. The presence of a systematic uncontrolled fungal, bacterial, viral or other infection (defined as the presence of signs/symptoms of infection without improvement despite antibiotics or other treatment). 5. Patients with uncontrolled autoimmune hemolytic anemia (AIHA) or autoimmune thrombocytopenia (ITP). 6. Patients with severe hematopoietic insufficiency as evidenced by an absolute neutrophil count of less than 500/µl and/or a platelet count of less than 30,000/µl at the time of the protocol. 7. Presence of any other severe comorbid disease or history of serious organ dysfunction, or disease affecting the heart, kidneys, liver, or other organs that would place the patient at undue risk when receiving Compound 1 and rituximab. 8. Presence of severe cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months. examination, or New York Heart Association Functional Classification grade 3 or 4 heart disease. 9. Presence of significant ECG abnormalities, including left atrioventricular bundle branch block, second-degree type II atrioventricular block, third-degree heart block, bradycardia, and a corrected QT interval >470 ms. 10. Presence of a serious medical condition, laboratory abnormality, or psychiatric illness that, in the opinion of the investigator, may place the patient at undue risk if he/she is to participate in the study. 11. The presence of a stroke or cerebral hemorrhage within 6 months. before the start of the study. 12. The presence of evidence of the presence of hemorrhagic diathesis or coagulopathy. 13. Radical surgery, surgical biopsy or major traumatic injury within 28 days before the first day of treatment, premature surgery during the study. 14. Presence of minor surgical procedures, diagnostic aspiration punctures, or core biopsy within 7 days prior to the first day of the study. Bone marrow aspiration and/or biopsy were acceptable. 15. The presence of a serious non-healing wound, ulcer or bone fracture. 16. Coumadin treatment. Patients who have recently taken Coumadin should have been off Coumadin for at least 7 days prior to

- 57 040198 start of the study. 17. No chemotherapy (eg, bendamustine, cyclophosphamide, pentostatin, or fludarabine), immunotherapy (eg, alemtuzumab or ofatumumab), bone marrow transplantation, experimental therapy, or radiotherapy is allowed during this study. 18. The use of drugs known to prolong the QTc interval or which may be associated with torsades de pointes (see Appendix F) is prohibited within 7 days prior to the start of the study drug study and during treatment with this drug.

All examples and variations described in this application are illustrative, and various modifications or changes proposed by experts in this field are included in the scope of this invention. As will be appreciated by those skilled in the art, the specific components listed in the above examples may be replaced by other functionally equivalent components, such as fillers, binders, lubricants, fillers, and the like.

Claims (49)

CLAIM 1. Crystalline Form A -en-1-one for which one or more of the following is true: (a) the crystalline form is characterized by X-ray powder diffraction (XRPD) with characteristic peaks at 2θ angle values of 5.7±0.1° obtained using CuKa radiation; (b) the crystalline form is characterized by XRPD with characteristic peaks at 2θ angle values of 18.9±0.1° obtained using CuKa radiation; (c) the crystalline form is characterized by XRPD with characteristic peaks at 2θ angle values of 21.3±0.1° obtained using CuKa radiation; (d) the crystalline form is characterized by XRPD with characteristic peaks as shown in FIG. 1; (e) the crystalline form is characterized by an infrared (IR) spectrum with bands with a frequency of 1584 cm ^-1 , 1240 cm ^-1 , 1147 cm ^-1 , 1134 cm ^-1 , 1099 cm ^-1 and 1067 cm ^-1 ; or (f) the crystalline form is characterized by a differential scanning calorimetry (DSC) thermogram peaking at 157° C., the DSC thermogram obtained by heating the crystalline form at a rate of 10° C./min. 2. Crystal form A according to claim 1, wherein the XRPD pattern contains a characteristic peak at 2θ angle values of 5.7 ± 0.1° obtained using CuKa radiation. 3. Crystal Form A according to claim 2, wherein the XRPD pattern further contains a characteristic peak at 2θ angle values of 13.6±0.1°. 4. Crystal Form A according to claim 2, wherein the XRPD pattern further contains a characteristic peak at 2θ angle values of 16.1±0.1°. 5. Crystal Form A according to claim 2, wherein the XRPD pattern further contains a characteristic peak at 2θ angle values of 18.9±0.1°. 6. Crystal Form A according to claim 2, wherein the XRPD pattern further contains a characteristic peak at 2θ angle values of 21.3 ± 0.1°. 7. Crystal form A according to claim 2, wherein the XRPD pattern further contains a characteristic peak at 2θ angle values of 21.6±0.1°. 8. Crystal Form A according to claim 5, wherein the XRPD pattern further contains a characteristic peak at 2θ angle values of 21.3 ± 0.1°. 9. Crystal Form A according to claim 8, wherein the XRPD pattern further contains a characteristic peak at 2θ angles of 13.6±0.1°, 16.1±0.1°, and 21.6±0.1°. 10. Crystal form A according to claim 1, wherein the XRPD pattern contains a characteristic peak at 2θ angle values of 18.9±0.1° obtained using CuKa radiation. 11. Crystal form A according to claim 10, wherein the XRPD pattern further comprises a characteristic peak at 2θ angle values of 13.6±0.1°. 12. Crystal form A according to claim 10, wherein the XRPD pattern further contains a characteristic peak at 2θ angle values of 16.1 ± 0.1°. 13. Crystal form A according to claim 10, wherein the XRPD pattern further contains a characteristic peak at 2θ angle values of 21.3 ± 0.1°. 14. Crystal form A according to claim 10, wherein the XRPD pattern further contains a characteristic peak at 2θ angle values of 13.6±0.1°. 15. Crystal form A according to claim 1, wherein the XRPD pattern further contains a characteristic peak at 2θ angle values of 16.1±0.1°. 16. Crystal form A according to claim 15, wherein the XRPD pattern further contains a characteristic peak at 2θ angle values of 21.6±0.1°. 17. Crystal form A according to claim 1, where the IR spectrum contains bands with a frequency of 1584 cm ^-1 , 1240 cm ^-1 , - 58 040198 1147 cm ^-1 , 1134 cm ^-1 , 1099 cm ^-1 and 1067 cm ^-1 . 18. The crystalline form A according to claim 1, wherein the DSC thermogram exhibits an endothermic effect peaking at 157°C, the DSC thermogram obtained by heating the crystalline form at a rate of 10°C/min. 19. Crystal form A according to claim 18, where the endothermic effect is observed starting from 154°C. 20. Crystalline form A according to claim 18, where an exothermic effect is additionally observed on the DSC thermogram at 159°C. 21. Crystal form A according to claim 18, wherein the thermogravimetric (TGA) curve of the crystal form is as shown in FIG. 4. 22. Crystal form A according to claim 1, for which one or more of the following is true: (a) powder X-ray pattern (XRPD) of the crystalline form does not change after storage at 40°C and relative humidity (RH) 75% for at least a week; (b) powder X-ray pattern (XRPD) of the crystalline form does not change after storage at 25°C and relative humidity (RH) 97% for at least a week; (c) the crystalline form is non-hygroscopic; or (d) the change in the mass of the crystalline form when measured by the method of dynamic vapor sorption (DVS) was less than 0.3% wt./weight. in the range of 0-90% RH. 23. The crystalline form A according to claim 1, wherein the crystalline form is unsolvated. 24. Pharmaceutical composition containing: (a) a crystalline form according to any one of claims 1 to 23; (b) a filler; and (c) a lubricant. 25. Pharmaceutical composition for oral administration, containing: (a) 40 to 200 mg of the crystalline form according to any one of claims 1 to 23; (b) 40 to 50% by weight of a filler; and (c) 0.2 to 1.0% by weight of a lubricant. 26. Pharmaceutical composition according to claim 25, additionally containing a baking powder. 27. Pharmaceutical composition according to claim 26, additionally containing a surfactant. 28. Pharmaceutical composition for oral administration, containing: (a) 40 to 200 mg of the crystalline form according to any one of claims 1 to 23; (b) from 40 to 50 wt.% filler; (c) from 3 to 10 wt.% baking powder; (d) 2 to 7% by weight of a surfactant; and (e) 0.2 to 1.0% by weight of a lubricant. 29. The pharmaceutical composition of claim 28, wherein the excipient is selected from lactose, sucrose, dextrose, dextrates, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrins, calcium phosphate, calcium sulfate, starches, modified starches, microcrystalline cellulose, microcellulose, and talc. 30. Pharmaceutical composition according to claim 29, wherein the excipient is microcrystalline cellulose. 31. Pharmaceutical composition according to claim 28, wherein the disintegrant is selected from natural starch, pregelatinized starch, sodium starch glycolate, crystalline methylcellulose, methylcellulose, croscarmellose, croscarmellose sodium, crosslinked sodium carboxymethylcellulose, crosslinked carboxymethylcellulose, crosslinked croscarmellose, crosslinked starch such as sodium starch glycolate, crosslinked polymer such as crospovidone, crosslinked polyvinylpyrrolidone, sodium alginate, clay and gum. 32. Pharmaceutical composition according to claim 28, wherein the disintegrant is selected from natural starch, pregelatinized starch, sodium starch glycolate, crystalline methylcellulose, methylcellulose, croscarmellose, croscarmellose sodium, crospovidone, sodium alginate, clay and gum. 33. The pharmaceutical composition according to claim 32, wherein the disintegrant is croscarmellose sodium. 34. The pharmaceutical composition of claim 28, wherein the surfactant is selected from sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, poloxamers, bile salts, glyceryl monostearate, ethylene oxide-propylene oxide copolymers. 35. The pharmaceutical composition according to claim 34, wherein the surfactant is sodium lauryl sulfate. 36. The pharmaceutical composition of claim 28, wherein the lubricant is selected from stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, sodium stearate, magnesium stearate, zinc stearate and waxes. - 59 040198 37. The pharmaceutical composition according to claim 36, wherein the lubricant is magnesium stearate. 38. The pharmaceutical composition of claim 27, wherein the excipient is selected from lactose, sucrose, dextrose, dextrates, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrins, calcium phosphate, calcium sulfate, starches, modified starches, microcrystalline cellulose, microcellulose, and talc; disintegrant selected from natural starch, pregelatinized starch, sodium starch glycolate, crystalline methylcellulose, methylcellulose, croscarmellose, croscarmellose sodium, crosslinked sodium carboxymethylcellulose, crosslinked carboxymethylcellulose, crosslinked croscarmellose, crosslinked starch such as sodium starch glycolate, crosslinked polymer, crosslinked polyvinylpyrrolidone, alginate sodium, clay or gum; the surfactant is selected from sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, poloxamers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide; and the lubricant is selected from stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, sodium stearate, magnesium stearate, zinc stearate and waxes. 39. Pharmaceutical composition for oral administration, containing: (a) from 40 to 50 wt.% of the crystalline form according to any one of paragraphs.1-23; (b) from 40 to 50 wt.% microcrystalline cellulose; (c) 3 to 10% by weight of croscarmellose sodium; (d) 2 to 7 wt% sodium lauryl sulfate; and (e) 0.2 to 1.0 wt% magnesium stearate. 40. Pharmaceutical composition for oral administration, containing: (a) 40 to 200 mg of the form according to any one of claims 1 to 23; (b) 40 to 50% by weight of microcrystalline cellulose; and (c) 0.2 to 1.0% by weight of magnesium stearate. 41. Pharmaceutical composition for oral administration, containing: (a) 40 to 200 mg of the crystalline form according to any one of claims 1 to 23; (b) from 40 to 50 wt.% microcrystalline cellulose; (c) 3 to 10% by weight of croscarmellose sodium; (d) 2 to 7 wt% sodium lauryl sulfate; and (e) 0.2 to 1.0 wt% magnesium stearate. 42. Pharmaceutical composition for oral administration, containing: (a) 140 mg of a crystalline form according to any one of claims 1 to 23; (b) 151.4 mg microcrystalline cellulose; (c) 23.0 mg croscarmellose sodium; (d) 14.0 mg sodium lauryl sulfate; and (e) 1.6 mg magnesium stearate. 43. Pharmaceutical composition for oral administration, containing: (a) 140 mg of a crystalline form according to any one of claims 1 to 23; (b) 45.9 wt% microcrystalline cellulose; (c) 7.0% by weight of croscarmellose sodium; (d) 4.2 wt% sodium lauryl sulfate; and (e) 0.5 wt% magnesium stearate. 44. A pharmaceutical composition according to any one of claims 24 to 43, wherein the pharmaceutical composition is in a dosage form which is a hard gelatin capsule. 45. Method for producing pharmaceutical composition 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1Hpyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop 2-en-1-one, comprising mixing one or more excipients with an isolated crystalline form according to any one of claims 1-23. 46. The method of claim 45, further comprising grinding the resulting mixture of one or more excipients and a crystalline form. 47. The method of claim 45, further comprising placing the mixture of one or more excipients and the crystalline form in a gelatin capsule. 48. The method of claim 45, further comprising placing a mixture of one or more excipients and crystalline form A in a non-gelatin capsule. 49. The method of claim 45, wherein the pharmaceutical composition is placed in a hard gelatin capsule.